Noise-cancellation algorithm for simulations of Brownian particles.

We investigate the usage of a recently introduced noise-cancellation algorithm for Brownian simulations to enhance the precision of measuring transport properties such as the mean-square displacement or the velocity-autocorrelation function. The algorithm is based on explicitly storing the pseudorandom numbers used to create the randomized displacements in computer simulations and subtracting them from the simulated trajectories. The resulting correlation function of the reduced motion is connected to the target correlation function up to a cross-correlation term. Using analytical theory and computer simulations, we demonstrate that the cross-correlation term can be neglected in all three systems studied in this paper. We further expand the algorithm to Monte Carlo simulations and analyze the performance of the algorithm and rationalize that it works particularly well for unbounded, weakly interacting systems in which the precision of the mean-square displacement can be improved by orders of magnitude.

Force renormalization for probes immersed in an active bath.

Langevin equations or generalized Langevin equations (GLEs) are popular models for describing the motion of a particle in a fluid medium in an effective manner. Here we examine particles immersed in an inherently nonequilibrium fluid, i.e., an active bath, which are subject to an external force. Specifically, we consider two types of forces that are highly relevant for microrheological studies: A harmonic, trapping force and a constant, "drag" force. We study such systems by molecular simulations and use the simulation data to extract an effective GLE description. We find that within this description, in an active bath, the external force in the GLE is not equal to the physical external force, but rather a renormalized external force, which can be significantly smaller. The effect cannot be attributed to the mere temperature renormalization, which is also observed.

Direct numerical simulations of a microswimmer in a viscoelastic fluid.

This study presents the application of the smoothed profile (SP) method to perform direct numerical simulations for the motion of both passive and active "squirming" particles in Newtonian and viscoelastic fluids. We found that fluid elasticity has a significant impact on both the transient behavior and the steady-state velocity of the particles. Specifically, we observe that the swirling flow generated by the squirmer's surface velocity significantly enhances their swimming speed as the Weissenberg number increases, regardless of the swimming type. Furthermore, we find that pushers outperform pullers in Oldroyd-B fluids, suggesting that the speed of a squirmer depends on the swimmer type. To understand the physical origin of the phenomenon of swirling flow enhancing the swimming speed, we investigate the velocity field and polymer conformation around non-swirling and swirling neutral squirmers in viscoelastic fluids. Our investigation reveals that the velocity field around the neutral swirling squirmers exhibits pusher-like extensional flow characteristics, as well as an asymmetric polymer conformation distribution, which gives rise to this increased propulsion. This is confirmed by the investigation of the force on a fixed squirmer, which revealed that the polymer stress, particularly its diagonal components, plays a critical role in enhancing the swimming speed of swirling squirmers in viscoelastic fluids. Additionally, our results demonstrate that the maximum swimming speeds of swirling squirmers occur at an intermediate value of the fluid viscosity ratio for all swimmer types. These findings have important implications for understanding the behavior of particles and micro-organisms in complex fluids.

Dynamic coarse-graining of linear and non-linear systems: Mori-Zwanzig formalism and beyond.

To investigate the impact of non-linear interactions on dynamic coarse graining, we study a simplified model system featuring a tracer particle in a complex environment. Using a projection operator formalism and computer simulations, we systematically derive generalized Langevin equations (GLEs) describing the dynamics of this particle. We compare different kinds of linear and non-linear coarse-graining procedures to understand how non-linearities enter reconstructed GLEs and how they influence the coarse-grained dynamics. For non-linear external potentials, we show analytically and numerically that the non-Gaussian parameter and the incoherent intermediate scattering function will not be correctly reproduced by the GLE if a linear projection is applied. This, however, can be overcome by using non-linear projection operators. We also study anharmonic coupling between the tracer and the environment and demonstrate that the reconstructed memory kernel develops an additional trap-dependent contribution. Our study highlights some open challenges and possible solutions in dynamic coarse graining.

Computer simulations and mode-coupling theory of glass-forming confined hard-sphere fluids.

We present mode-coupling theory (MCT) results for densely packed hard-sphere fluids confined between two parallel walls and compare them quantitatively to computer simulations. The numerical solution of MCT is calculated using the full system of matrix-valued integro-differential equations. We investigate several dynamical properties of supercooled liquids including scattering functions, frequency-dependent susceptibilities, and mean-square displacements. Close to the glass transition, we find quantitative agreement between the coherent scattering function predicted from theory and that evaluated from simulations, which enables us to make quantitative statements on caging and relaxation dynamics of the confined hard-sphere fluid.

Predicting Dynamic Heterogeneity in Glass-Forming Liquids by Physics-Inspired Machine Learning.

We introduce GlassMLP, a machine learning framework using physics-inspired structural input to predict the long-time dynamics in deeply supercooled liquids. We apply this deep neural network to atomistic models in 2D and 3D. Its performance is better than the state of the art while being more parsimonious in terms of training data and fitting parameters. GlassMLP quantitatively predicts four-point dynamic correlations and the geometry of dynamic heterogeneity. Transferability across system sizes allows us to efficiently probe the temperature evolution of spatial dynamic correlations, revealing a profound change with temperature in the geometry of rearranging regions.

Stability of Branched Tubular Membrane Structures.

We study the energetics and stability of branched tubular membrane structures by computer simulations of a triangulated network model. We find that triple (Y) junctions can be created and stabilized by applying mechanical forces, if the angle between branches is 120°. The same holds for tetrahedral junctions with tetraeder angles. If the wrong angles are enforced, the branches coalesce to a linear structure, a pure tube. After releasing the mechanical force, Y-branched structures remain metastable if one constrains the enclosed volume and the average curvature (the area difference) to a fixed value; tetrahedral junctions however split up into two Y junctions. Somewhat counterintuitively, the energy cost of adding a Y branch is negative in structures with fixed surface area and tube diameter, even if one accounts for the positive contribution of the additional branch end. For fixed average curvature, however, adding a branch also enforces a thinning of tubes, therefore the overall curvature energy cost is positive. Possible implications for the stability of branched networks structures in cells are discussed.

Passive probe particle in an active bath: can we tell it is out of equilibrium?

We study a passive probe immersed in a fluid of active particles. Despite the system's non-equilibrium nature, the trajectory of the probe does not exhibit non-equilibrium signatures: its velocity distribution remains Gaussian, the second fluctuation dissipation theorem is not fundamentally violated, and the motion does not indicate breaking of time reversal symmetry. To tell that the probe is out of equilibrium requires examination of its behavior in tandem with that of the active fluid: the kinetic temperature of the probe does not equilibrate to that of the surrounding active particles. As a strategy to diagnose non-equilibrium from probe trajectories alone, we propose to examine their response to a small perturbation which reveals a non-equilibrium signature through a violation of the first fluctuation dissipation theorem.

Structural properties of liquids in extreme confinement.

We simulate a hard-sphere liquid in confined geometry where the separation of the two parallel, hard walls is smaller than two particle diameters. By systematically reducing the wall separation we analyze the behavior of structural and thermodynamic properties, such as inhomogeneous density profiles, structure factors, and compressibilities when approaching the two-dimensional limit. In agreement with asymptotic predictions, we find for quasi-two-dimensional fluids that the density profile becomes parabolic and the structure factor converges toward its two-dimensional counterpart. To extract the compressibility in polydisperse samples a perturbative expression is used which qualitatively influences the observed nonmonotonic dependence of the compressibility with wall separation. We also present theoretical calculations based on fundamental-measure theory and integral-equation theory, which are in very good agreement with the simulation results.

Layering and packing in confined colloidal suspensions.

Confinement modifies the properties of a fluid. The particle density is no longer uniform but depends on the distance from the walls; parallel to the walls, layers with different particle densities form. This affects the particle packing in the layers. We investigated colloidal fluids with volume fractions between 0.19 and 0.32 confined between rough walls. The particle-particle interactions were dominated by hard-sphere interactions but also contained some electrostatic interactions. The particle locations were determined using confocal microscopy and served to calculate the density profile, radial distribution function, anisotropic and generalized structure factors but also to characterize the arrangement of the wall particles leading to the roughness of the walls. The experiments are complemented by molecular dynamics simulations and fundamental-measure theory. While the particle arrangements are mainly controlled by hard-core interactions, electrostatic interactions become more important as the volume fraction decreases. Furthermore, the structure of the rough walls was varied and found to have a significant effect on the fluid structure. An appropriate representation of the rough walls in the simulations is thus crucial to successfully mimic the experiments.

Epigenome-Wide DNA Methylation Profiling of Normal Mucosa Reveals HLA-F Hypermethylation as a Biomarker Candidate for Serrated Polyposis Syndrome.

Serrated polyposis syndrome (SPS) is associated with a high risk for colorectal cancer. Intense promoter hypermethylation is a frequent molecular finding in the serrated pathway and may be present in normal mucosa, predisposing to the formation of serrated lesions. To identify novel biomarkers for SPS, fresh-frozen samples of normal mucosa from 50 patients with SPS and 19 healthy individuals were analyzed by using the 850K BeadChip Technology (Infinium). Aberrant methylation levels were correlated with gene expression using a next-generation transcriptome profiling tool. Two validation steps were performed on independent cohorts: first, on formalin-fixed, paraffin-embedded tissue of the normal mucosa; and second, on 24 serrated lesions. The most frequently hypermethylated genes were HLA-F, SLFN12, HLA-DMA, and RARRES3; and the most frequently hypomethylated genes were PIWIL1 and ANK3 (Δß = 10%; P < 0.05). Expression levels of HLA-F, SLFN12, and HLA-DMA were significantly different between SPS patients and healthy individuals and correlated well with the methylation status of the corresponding differentially methylated region (fold change, >20%; r > 0.55; P < 0.001). Significant hypermethylation of CpGs in the gene body of HLA-F was also found in serrated lesions (Δß = 23%; false discovery rate = 0.01). Epigenome-wide methylation profiling has revealed numerous differentially methylated CpGs in normal mucosa from SPS patients. Significant hypermethylation of HLA-F is a novel biomarker candidate for SPS.

Differentially Deregulated MicroRNAs as Novel Biomarkers for Neoplastic Progression in Ulcerative Colitis.

INTRODUCTION: Colorectal cancer (CRC) is a potentially life-threatening complication of long-standing ulcerative colitis (UC). MicroRNAs (miRNA) are epigenetic regulators that have been involved in the development of UC-associated CRC. However, their role as potential mucosal biomarkers of neoplastic progression has not been adequately studied. METHODS: In this study, we analyzed the expression of 96 preselected miRNAs in human formalin-fixed and paraffin-embedded tissue of 52 case biopsies (20 normal mucosa, 20 dysplasia, and 12 UC-associated CRCs) and 50 control biopsies (10 normal mucosa, 21 sporadic adenomas, and 19 sporadic CRCs) by using Custom TaqMan Array Cards. For validation of deregulated miRNAs, we performed individual quantitative real-time polymerase chain reaction in an independent cohort of 50 cases (13 normal mucosa, 25 dysplasia, and 12 UC-associated CRCs) and 46 controls (7 normal mucosa, 19 sporadic adenomas, and 20 sporadic CRCs). RESULTS: Sixty-four miRNAs were found to be differentially deregulated in the UC-associated CRC sequence. Eight of these miRNAs were chosen for further validation. We confirmed miR-31, -106a, and -135b to be significantly deregulated between normal mucosa and dysplasia, as well as across the UC-associated CRC sequence (all P < 0.01). Notably, these miRNAs also confirmed to have a significant differential expression compared with sporadic CRC (all P < 0.05). DISCUSSION: UC-associated and sporadic CRCs have distinct miRNA expression patterns, and some miRNAs indicate early neoplastic progression.

Non-Markovian systems out of equilibrium: exact results for two routes of coarse graining.

Generalized Langevin equations (GLEs) can be systematically derived via dimensional reduction from high-dimensional microscopic systems. For linear models the derivation can either be based on projection operator techniques such as the Mori-Zwanzig (MZ) formalism or by 'integrating out' the bath degrees of freedom. Based on exact analytical results we show that both routes can lead to fundamentally different GLEs and that the origin of these differences is based inherently on the non-equilibrium nature of the microscopic stochastic model. The most important conceptional difference between the two routes is that the MZ result intrinsically fulfills the generalized second fluctuation-dissipation theorem while the integration result can lead to its violation. We supplement our theoretical findings with numerical and simulation results for two popular non-equilibrium systems: time-delayed feedback control and the active Ornstein-Uhlenbeck process.

Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome.

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and pan-chromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

The "diagnose and leave in" strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial.

BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %-98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %-93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

Prevalence of adenomatous polyposis in a fecal immunochemical test-based colorectal cancer screening program and risk of advanced neoplasia during follow-up.

BACKGROUND : Current guidelines recommend genetic counseling and intensive colonoscopy surveillance for patients with ≥ 10 colorectal adenomas based on scarce data. We investigated the prevalence of this condition in a fecal immunochemical test (FIT)-based colorectal (CRC) screening program, and the incidence of metachronous lesions during follow-up. METHODS: We retrospectively included all FIT-positive participants with ≥ 10 adenomas at index colonoscopy between 2010 and 2018. Surveillance colonoscopies were collected until 2019. Patients with inherited syndromes, serrated polyposis syndrome, total colectomy, or lacking surveillance data were excluded. The cumulative incidence of CRC and advanced neoplasia were analyzed by Kaplan-Meier analysis. Risk factors for metachronous advanced neoplasia were investigated by multivariable logistic regression analysis. RESULTS: 215 of 9582 participants (2.2 %) had ≥ 10 adenomas. Germline genetic testing was performed in 92 % of patients with ≥ 20 adenomas, identifying two inherited syndromes (3.3 %). The 3-year cumulative incidence of CRC and advanced neoplasia were 1 % and 16 %, respectively. In 39 patients (24.2 %), no polyps were found on first surveillance colonoscopy. The presence of an advanced adenoma was independently associated with a higher risk of advanced neoplasia at first surveillance colonoscopy (odds ratio 3.91, 95 %CI 1.12-13.62; P = 0.03). Beyond the first surveillance colonoscopy, the risk of metachronous advanced neoplasia was lower. CONCLUSIONS: The prevalence of ≥ 10 adenomas in a FIT-based CRC screening program was 2.2 %; a small proportion of inherited syndromes were detected, even amongst those with ≥ 20 adenomas. A low rate of post-colonoscopy CRC was observed and the risk of advanced neoplasia beyond the first surveillance colonoscopy tended to progressively decrease throughout successive follow-ups.

Identification of Lynch Syndrome Carriers among Patients with Small Bowel Adenocarcinoma.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR deficient (MMRd) tumors varies from 5% to 35%. This study aims to describe the prevalence of LS carriers among patients with MMRd small bowel adenocarcinomas. METHODS: A multicenter retrospective study with identification and MMR testing of all consecutive SBA between 2004 and 2020 in a multicenter Spanish study. Demographical data, tumor characteristics, follow-up and survival information were collected. Germline testing was driven by identification of MMRd tumors. RESULTS: A total of 94 individuals diagnosed with SBA were recruited. We observed 20 (21.3%) MMRd tumors. In 9/15 (60%) patients with MMRd tumors, a pathogenic variant was identified (three MLH1, four MSH2, one MSH6 and one PMS2). Accordingly, the prevalence of LS among all SBA cases was 10.1%. CONCLUSIONS: More than one-fifth of SBA display MMRd and in more than a half is due to LS. Our data supports the implementation of universal MMR tumor testing among SBA for the identification of LS families.

Vaccines for Non-Viral Cancer Prevention.

Cancer vaccines are a type of immune therapy that seeks to modulate the host's immune system to induce durable and protective immune responses against cancer-related antigens. The little clinical success of therapeutic cancer vaccines is generally attributed to the immunosuppressive tumor microenvironment at late-stage diseases. The administration of cancer-preventive vaccination at early stages, such as pre-malignant lesions or even in healthy individuals at high cancer risk could increase clinical efficacy by potentiating immune surveillance and pre-existing specific immune responses, thus eliminating de novo appearing lesions or maintaining equilibrium. Indeed, research focus has begun to shift to these approaches and some of them are yielding encouraging outcomes.

Fluctuation-dissipation relations far from equilibrium: a case study.

Fluctuation-dissipation relations or "theorems" (FDTs) are fundamental for statistical physics and can be rigorously derived for equilibrium systems. Their applicability to non-equilibrium systems is, however, debated. Here, we simulate an active microrheology experiment, in which a spherical colloid is pulled with a constant external force through a fluid, creating near-equilibrium and far-from-equilibrium systems. We characterize the structural and dynamical properties of these systems, and reconstruct an effective generalized Langevin equation (GLE) for the colloid dynamics. Specifically, we test the validity of two FDTs: The first FDT relates the non-equilibrium response of a system to equilibrium correlation functions, and the second FDT relates the memory friction kernel in the GLE to the stochastic force. We find that the validity of the first FDT depends strongly on the strength of the external driving: it is fulfilled close to equilibrium and breaks down far from it. In contrast, we observe that the second FDT is always fulfilled. We provide a mathematical argument why this generally holds for memory kernels reconstructed from a deterministic Volterra equation for correlation functions, even for non-stationary non-equilibrium systems. Motivated by the Mori-Zwanzig formalism, we therefore suggest to impose an orthogonality constraint on the stochastic force, which is in fact equivalent to the validity of this Volterra equation. Such GLEs automatically satisfy the second FDT and are unique, which is desirable when using GLEs for coarse-grained modeling.

Introducing Memory in Coarse-Grained Molecular Simulations.

Preserving the correct dynamics at the coarse-grained (CG) level is a pressing problem in the development of systematic CG models in soft matter simulation. Starting from the seminal idea of simple time-scale mapping, there have been many efforts over the years toward establishing a meticulous connection between the CG and fine-grained (FG) dynamics based on fundamental statistical mechanics approaches. One of the most successful attempts in this context has been the development of CG models based on the Mori-Zwanzig (MZ) theory, where the resulting equation of motion has the form of a generalized Langevin equation (GLE) and closely preserves the underlying FG dynamics. In this Review, we describe some of the recent studies in this regard. We focus on the construction and simulation of dynamically consistent systematic CG models based on the GLE, both in the simple Markovian limit and the non-Markovian case. Some recent studies of physical effects of memory are also discussed. The Review is aimed at summarizing recent developments in the field while highlighting the major challenges and possible future directions.