Label-free nanofluidic scattering microscopy of size and mass of single diffusing molecules and nanoparticles.

Label-free characterization of single biomolecules aims to complement fluorescence microscopy in situations where labeling compromises data interpretation, is technically challenging or even impossible. However, existing methods require the investigated species to bind to a surface to be visible, thereby leaving a large fraction of analytes undetected. Here, we present nanofluidic scattering microscopy (NSM), which overcomes these limitations by enabling label-free, real-time imaging of single biomolecules diffusing inside a nanofluidic channel. NSM facilitates accurate determination of molecular weight from the measured optical contrast and of the hydrodynamic radius from the measured diffusivity, from which information about the conformational state can be inferred. Furthermore, we demonstrate its applicability to the analysis of a complex biofluid, using conditioned cell culture medium containing extracellular vesicles as an example. We foresee the application of NSM to monitor conformational changes, aggregation and interactions of single biomolecules, and to analyze single-cell secretomes.

Dynamic multilayer functional connectivity detects preclinical and clinical Alzheimer's disease.

Increasing evidence suggests that patients with Alzheimer's disease present alterations in functional connectivity but previous results have not always been consistent. One of the reasons that may account for this inconsistency is the lack of consideration of temporal dynamics. To address this limitation, here we studied the dynamic modular organization on resting-state functional magnetic resonance imaging across different stages of Alzheimer's disease using a novel multilayer brain network approach. Participants from preclinical and clinical Alzheimer's disease stages were included. Temporal multilayer networks were used to assess time-varying modular organization. Logistic regression models were employed for disease stage discrimination, and partial least squares analyses examined associations between dynamic measures with cognition and pathology. Temporal multilayer functional measures distinguished all groups, particularly preclinical stages, overcoming the discriminatory power of risk factors such as age, sex, and APOE ϵ4 carriership. Dynamic multilayer functional measures exhibited strong associations with cognition as well as amyloid and tau pathology. Dynamic multilayer functional connectivity shows promise as a functional imaging biomarker for both early- and late-stage Alzheimer's disease diagnosis.

Dual-Angle Interferometric Scattering Microscopy for Optical Multiparametric Particle Characterization.

Traditional single-nanoparticle sizing using optical microscopy techniques assesses size via the diffusion constant, which requires suspended particles to be in a medium of known viscosity. However, these assumptions are typically not fulfilled in complex natural sample environments. Here, we introduce dual-angle interferometric scattering microscopy (DAISY), enabling optical quantification of both size and polarizability of individual nanoparticles (radius <170 nm) without requiring a priori information regarding the surrounding media or super-resolution imaging. DAISY achieves this by combining the information contained in concurrently measured forward and backward scattering images through twilight off-axis holography and interferometric scattering (iSCAT). Going beyond particle size and polarizability, single-particle morphology can be deduced from the fact that the hydrodynamic radius relates to the outer particle radius, while the scattering-based size estimate depends on the internal mass distribution of the particles. We demonstrate this by differentiating biomolecular fractal aggregates from spherical particles in fetal bovine serum at the single-particle level.

Destructive effect of fluctuations on the performance of a Brownian gyrator.

The Brownian gyrator (BG) is often called a minimal model of a nano-engine performing a rotational motion, judging solely upon the fact that in non-equilibrium conditions its torque, specific angular momentum  and specific angular velocity  have non-zero mean values. For a time-discretised (with time-step δt) model we calculate here the previously unknown probability density functions (PDFs) of  and . We show that for finite δt, the PDF of  has exponential tails and all moments are therefore well-defined. At the same time, this PDF appears to be effectively broad - the noise-to-signal ratio is generically bigger than unity meaning that  is strongly not self-averaging. Concurrently, the PDF of  exhibits heavy power-law tails and its mean is the only existing moment. The BG is therefore not an engine in the common sense: it does not exhibit regular rotations on each run and its fluctuations are not only a minor nuisance - on contrary, their effect is completely destructive for the performance. Our theoretical predictions are confirmed by numerical simulations and experimental data. We discuss some plausible improvements of the model which may result in a more systematic rotational motion.

Intercellular communication induces glycolytic synchronization waves between individually oscillating cells.

Many organs have internal structures with spatially differentiated and sometimes temporally synchronized groups of cells. The mechanisms leading to such differentiation and coordination are not well understood. Here we design a diffusion-limited microfluidic system to mimic a multicellular organ structure with peripheral blood flow and test whether a group of individually oscillating yeast cells could form subpopulations of spatially differentiated and temporally synchronized cells. Upon substrate addition, the dynamic response at single-cell level shows glycolytic oscillations, leading to wave fronts traveling through the monolayered population and to synchronized communities at well-defined positions in the cell chamber. A detailed mechanistic model with the architectural structure of the flow chamber incorporated successfully predicts the spatial-temporal experimental data, and allows for a molecular understanding of the observed phenomena. The intricate interplay of intracellular biochemical reaction networks leading to the oscillations, combined with intercellular communication via metabolic intermediates and fluid dynamics of the reaction chamber, is responsible for the generation of the subpopulations of synchronized cells. This mechanism, as analyzed from the model simulations, is experimentally tested using different concentrations of cyanide stress solutions. The results are reproducible and stable, despite cellular heterogeneity, and the spontaneous community development is reminiscent of a zoned cell differentiation often observed in multicellular organs.

CT-based volumetric measures obtained through deep learning: Association with biomarkers of neurodegeneration.

INTRODUCTION: Cranial computed tomography (CT) is an affordable and widely available imaging modality that is used to assess structural abnormalities, but not to quantify neurodegeneration. Previously we developed a deep-learning-based model that produced accurate and robust cranial CT tissue classification. MATERIALS AND METHODS: We analyzed 917 CT and 744 magnetic resonance (MR) scans from the Gothenburg H70 Birth Cohort, and 204 CT and 241 MR scans from participants of the Memory Clinic Cohort, Singapore. We tested associations between six CT-based volumetric measures (CTVMs) and existing clinical diagnoses, fluid and imaging biomarkers, and measures of cognition. RESULTS: CTVMs differentiated cognitively healthy individuals from dementia and prodromal dementia patients with high accuracy levels comparable to MR-based measures. CTVMs were significantly associated with measures of cognition and biochemical markers of neurodegeneration. DISCUSSION: These findings suggest the potential future use of CT-based volumetric measures as an informative first-line examination tool for neurodegenerative disease diagnostics after further validation. HIGHLIGHTS: Computed tomography (CT)-based volumetric measures can distinguish between patients with neurodegenerative disease and healthy controls, as well as between patients with prodromal dementia and controls. CT-based volumetric measures associate well with relevant cognitive, biochemical, and neuroimaging markers of neurodegenerative diseases. Model performance, in terms of brain tissue classification, was consistent across two cohorts of diverse nature. Intermodality agreement between our automated CT-based and established magnetic resonance (MR)-based image segmentations was stronger than the agreement between visual CT and MR imaging assessment.

Peripheral inflammatory subgroup differences in anterior Default Mode network and multiplex functional network topology are associated with cognition in psychosis.

INTRODUCTION: High-inflammation subgroups of patients with psychosis demonstrate cognitive deficits and neuroanatomical alterations. Systemic inflammation assessed using IL-6 and C-reactive protein may alter functional connectivity within and between resting-state networks, but the cognitive and clinical implications of these alterations remain unknown. We aim to determine the relationships of elevated peripheral inflammation subgroups with resting-state functional networks and cognition in psychosis spectrum disorders. METHODS: Serum and resting-state fMRI were collected from psychosis probands (schizophrenia, schizoaffective, psychotic bipolar disorder) and healthy controls (HC) from the B-SNIP1 (Chicago site) study who were stratified into inflammatory subgroups based on factor and cluster analyses of 13 cytokines (HC Low n = 32, Proband Low n = 65, Proband High n = 29). Nine resting-state networks derived from independent component analysis were used to assess functional and multilayer connectivity. Inter-network connectivity was measured using Fisher z-transformation of correlation coefficients. Network organization was assessed by investigating networks of positive and negative connections separately, as well as investigating multilayer networks using both positive and negative connections. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia. Linear regressions, Spearman correlations, permutations tests and multiple comparison corrections were used for analyses in R. RESULTS: Anterior default mode network (DMNa) connectivity was significantly reduced in the Proband High compared to Proband Low (Cohen's d = -0.74, p = 0.002) and HC Low (d = -0.85, p = 0.0008) groups. Inter-network connectivity between the DMNa and the right-frontoparietal networks was lower in Proband High compared to Proband Low (d = -0.66, p = 0.004) group. Compared to Proband Low, the Proband High group had lower negative (d = 0.54, p = 0.021) and positive network (d = 0.49, p = 0.042) clustering coefficient, and lower multiplex network participation coefficient (d = -0.57, p = 0.014). Network findings in high inflammation subgroups correlate with worse verbal fluency, verbal memory, symbol coding, and overall cognition. CONCLUSION: These results expand on our understanding of the potential effects of peripheral inflammatory signatures and/or subgroups on network dysfunction in psychosis and how they relate to worse cognitive performance. Additionally, the novel multiplex approach taken in this study demonstrated how inflammation may disrupt the brain's ability to maintain healthy co-activation patterns between the resting-state networks while inhibiting certain connections between them.

Directed Brain Connectivity Identifies Widespread Functional Network Abnormalities in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by topological abnormalities in large-scale functional brain networks, which are commonly analyzed using undirected correlations in the activation signals between brain regions. This approach assumes simultaneous activation of brain regions, despite previous evidence showing that brain activation entails causality, with signals being typically generated in one region and then propagated to other ones. To address this limitation, here, we developed a new method to assess whole-brain directed functional connectivity in participants with PD and healthy controls using antisymmetric delayed correlations, which capture better this underlying causality. Our results show that whole-brain directed connectivity, computed on functional magnetic resonance imaging data, identifies widespread differences in the functional networks of PD participants compared with controls, in contrast to undirected methods. These differences are characterized by increased global efficiency, clustering, and transitivity combined with lower modularity. Moreover, directed connectivity patterns in the precuneus, thalamus, and cerebellum were associated with motor, executive, and memory deficits in PD participants. Altogether, these findings suggest that directional brain connectivity is more sensitive to functional network differences occurring in PD compared with standard methods, opening new opportunities for brain connectivity analysis and development of new markers to track PD progression.

Multiplex Connectome Changes across the Alzheimer's Disease Spectrum Using Gray Matter and Amyloid Data.

The organization of the Alzheimer's disease (AD) connectome has been studied using graph theory using single neuroimaging modalities such as positron emission tomography (PET) or structural magnetic resonance imaging (MRI). Although these modalities measure distinct pathological processes that occur in different stages in AD, there is evidence that they are not independent from each other. Therefore, to capture their interaction, in this study we integrated amyloid PET and gray matter MRI data into a multiplex connectome and assessed the changes across different AD stages. We included 135 cognitively normal (CN) individuals without amyloid-ß pathology (Aß-) in addition to 67 CN, 179 patients with mild cognitive impairment (MCI) and 132 patients with AD dementia who all had Aß pathology (Aß+) from the Alzheimer's Disease Neuroimaging Initiative. We found widespread changes in the overlapping connectivity strength and the overlapping connections across Aß-positive groups. Moreover, there was a reorganization of the multiplex communities in MCI Aß + patients and changes in multiplex brain hubs in both MCI Aß + and AD Aß + groups. These findings offer a new insight into the interplay between amyloid-ß pathology and brain atrophy over the course of AD that moves beyond traditional graph theory analyses based on single brain networks.

Perspectives on adaptive dynamical systems.

Adaptivity is a dynamical feature that is omnipresent in nature, socio-economics, and technology. For example, adaptive couplings appear in various real-world systems, such as the power grid, social, and neural networks, and they form the backbone of closed-loop control strategies and machine learning algorithms. In this article, we provide an interdisciplinary perspective on adaptive systems. We reflect on the notion and terminology of adaptivity in different disciplines and discuss which role adaptivity plays for various fields. We highlight common open challenges and give perspectives on future research directions, looking to inspire interdisciplinary approaches.

Age-related differences in network structure and dynamic synchrony of cognitive control.

Cognitive trajectories vary greatly across older individuals, and the neural mechanisms underlying these differences remain poorly understood. Here, we investigate the cognitive variability in older adults by linking the influence of white matter microstructure on the task-related organization of fast and effective communications between brain regions. Using diffusion tensor imaging and electroencephalography, we show that individual differences in white matter network organization are associated with network clustering and efficiency in the alpha and high-gamma bands, and that functional network dynamics partly explain individual differences in cognitive control performance in older adults. We show that older individuals with high versus low structural network clustering differ in task-related network dynamics and cognitive performance. These findings were corroborated by investigating magnetoencephalography networks in an independent dataset. This multimodal (fMRI and biological markers) brain connectivity framework of individual differences provides a holistic account of how differences in white matter microstructure underlie age-related variability in dynamic network organization and cognitive performance.

Deep learning from MRI-derived labels enables automatic brain tissue classification on human brain CT.

Automatic methods for feature extraction, volumetry, and morphometric analysis in clinical neuroscience typically operate on images obtained with magnetic resonance (MR) imaging equipment. Although CT scans are less expensive to acquire and more widely available than MR scans, their application is currently limited to the visual assessment of brain integrity and the exclusion of co-pathologies. CT has rarely been used for tissue classification because the contrast between grey matter and white matter was considered insufficient. In this study, we propose an automatic method for segmenting grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), and intracranial volume (ICV) from head CT images. A U-Net deep learning model was trained and validated on CT images with MRI-derived segmentation labels. We used data from 744 participants of the Gothenburg H70 Birth Cohort Studies for whom CT and T1-weighted MR images had been acquired on the same day. Our proposed model predicted brain tissue classes accurately from unseen CT images (Dice coefficients of 0.79, 0.82, 0.75, 0.93 and 0.98 for GM, WM, CSF, brain volume and ICV, respectively). To contextualize these results, we generated benchmarks based on established MR-based methods and intentional image degradation. Our findings demonstrate that CT-derived segmentations can be used to delineate and quantify brain tissues, opening new possibilities for the use of CT in clinical practice and research.

Anisotropic dynamics of a self-assembled colloidal chain in an active bath.

Anisotropic macromolecules exposed to non-equilibrium (active) noise are very common in biological systems, and an accurate understanding of their anisotropic dynamics is therefore crucial. Here, we experimentally investigate the dynamics of isolated chains assembled from magnetic microparticles at a liquid-air interface and moving in an active bath consisting of motile E. coli bacteria. We investigate both the internal chain dynamics and the anisotropic center-of-mass dynamics through particle tracking. We find that both the internal and center-of-mass dynamics are greatly enhanced compared to the passive case, i.e., a system without bacteria, and that the center-of-mass diffusion coefficient D features a non-monotonic dependence as a function of the chain length. Furthermore, our results show that the relationship between the components of D parallel and perpendicular with respect to the direction of the applied magnetic field is preserved in the active bath compared to the passive case, with a higher diffusion in the parallel direction, in contrast to previous findings in the literature. We argue that this qualitative difference is due to subtle differences in the experimental geometry and conditions and the relative roles played by long-range hydrodynamic interactions and short-range collisions.

Correction: Controlling the dynamics of colloidal particles by critical Casimir forces.

Correction for 'Controlling the dynamics of colloidal particles by critical Casimir forces' by Alessandro Magazzù et al., Soft Matter, 2019, 15, 2152-2162, DOI: 10.1039/C8SM01376D.

Ordering of binary colloidal crystals by random potentials.

Structural defects are ubiquitous in condensed matter, and not always a nuisance. For example, they underlie phenomena such as Anderson localization and hyperuniformity, and they are now being exploited to engineer novel materials. Here, we show experimentally that the density of structural defects in a 2D binary colloidal crystal can be engineered with a random potential. We generate the random potential using an optical speckle pattern, whose induced forces act strongly on one species of particles (strong particles) and weakly on the other (weak particles). Thus, the strong particles are more attracted to the randomly distributed local minima of the optical potential, leaving a trail of defects in the crystalline structure of the colloidal crystal. While, as expected, the crystalline ordering initially decreases with an increasing fraction of strong particles, the crystalline order is surprisingly recovered for sufficiently large fractions. We confirm our experimental results with particle-based simulations, which permit us to elucidate how this non-monotonic behavior results from the competition between the particle-potential and particle-particle interactions.

The topography of the environment alters the optimal search strategy for active particles.

In environments with scarce resources, adopting the right search strategy can make the difference between succeeding and failing, even between life and death. At different scales, this applies to molecular encounters in the cell cytoplasm, to animals looking for food or mates in natural landscapes, to rescuers during search and rescue operations in disaster zones, and to genetic computer algorithms exploring parameter spaces. When looking for sparse targets in a homogeneous environment, a combination of ballistic and diffusive steps is considered optimal; in particular, more ballistic Lévy flights with exponent [Formula: see text] are generally believed to optimize the search process. However, most search spaces present complex topographies. What is the best search strategy in these more realistic scenarios? Here, we show that the topography of the environment significantly alters the optimal search strategy toward less ballistic and more Brownian strategies. We consider an active particle performing a blind cruise search for nonregenerating sparse targets in a 2D space with steps drawn from a Lévy distribution with the exponent varying from [Formula: see text] to [Formula: see text] (Brownian). We show that, when boundaries, barriers, and obstacles are present, the optimal search strategy depends on the topography of the environment, with [Formula: see text] assuming intermediate values in the whole range under consideration. We interpret these findings using simple scaling arguments and discuss their robustness to varying searcher's size. Our results are relevant for search problems at different length scales from animal and human foraging to microswimmers' taxis to biochemical rates of reaction.

A Preventive Program for Work-related Musculoskeletal Disorders Among Surgeons: Outcomes of a Randomized Controlled Clinical Trial.

OBJECTIVE: To evaluate the effectiveness of a program to reduce work-related musculoskeletal disorders (WRMSD) among surgeons. BACKGROUND: Surgeons are at high risk of WRMSD due to many physical and psychosocial factors. METHODS: This study is a multicenter randomized clinical trial (UMIN000028557) conducted from January to August 2015. Following cluster randomization by surgical division, surgeons were allocated to 2 groups. The NPP group (No Preventive Program) underwent no intervention, while the PP group (Preventive Program) followed ergonomic principles in the operating room and specific physical exercises supervised by a physical therapist. A multiple logistic regression was performed to identify baseline WRMSD risk factors. WRMSD assessment was based on 1 ad hoc and 3 validated questionnaires: Nordic Musculoskeletal Questionnaire (NMQ), Numerical Rating Scale (NRS), and Short Form 36 Health Survey (SF-36). Follow-up was planned after 3 and 6 months. RESULTS: One hundred forty-one surgeons matched the inclusion criteria and were randomized in the PP (n = 65) and NPP (n = 76) groups. At the initial analysis, physical activity was the only modifiable independent risk factor for WRMSD (OR, 2.44; P = 0.05). The PP group showed a significant improvement in the item "General Health" (GH) regarding quality of life at 3 (NPP: 70.5 ±â€Š15.2 vs PP: 75.9 ±â€Š14.1; P = 0.04) and 6 months (70.6 ±â€Š13.4 vs 75.3 ±â€Š13.0; P = 0.04). The PP group had a significant reduction of low back pain (66.2% vs 50.0%; P = 0.04) and analgesic consumption (30.9% vs 15.5%; P = 0.03) after 6 months. CONCLUSIONS: This study demonstrated the effectiveness of a global program based on the application of ergonomics in the operating room and specific physical exercises.

Controlling the dynamics of colloidal particles by critical Casimir forces.

Critical Casimir forces can play an important role for applications in nano-science and nano-technology, owing to their piconewton strength, nanometric action range, fine tunability as a function of temperature, and exquisite dependence on the surface properties of the involved objects. Here, we investigate the effects of critical Casimir forces on the free dynamics of a pair of colloidal particles dispersed in the bulk of a near-critical binary liquid solvent, using blinking optical tweezers. In particular, we measure the time evolution of the distance between the two colloids to determine their relative diffusion and drift velocity. Furthermore, we show how critical Casimir forces change the dynamic properties of this two-colloid system by studying the temperature dependence of the distribution of the so-called first-passage time, i.e., of the time necessary for the particles to reach for the first time a certain separation, starting from an initially assigned one. These data are in good agreement with theoretical results obtained from Monte Carlo simulations and Langevin dynamics.

Clustering of Janus particles in an optical potential driven by hydrodynamic fluxes.

Self-organisation is driven by the interactions between the individual components of a system mediated by the environment, and is one of the most important strategies used by many biological systems to develop complex and functional structures. Furthermore, biologically-inspired self-organisation offers opportunities to develop the next generation of materials and devices for electronics, photonics and nanotechnology. In this work, we demonstrate experimentally that a system of Janus particles (silica microspheres half-coated with gold) aggregates into clusters in the presence of a Gaussian optical potential and disaggregates when the optical potential is switched off. We show that the underlying mechanism is the existence of a hydrodynamic flow induced by a temperature gradient generated by the light absorption at the metallic patches on the Janus particles. We also perform simulations, which agree well with the experiments and whose results permit us to clarify the underlying mechanism. The possibility of hydrodynamic-flux-induced reversible clustering may have applications in the fields of drug delivery, cargo transport, bioremediation and biopatterning.

Active matter alters the growth dynamics of coffee rings.

How particles are deposited at the edge of evaporating droplets, i.e. the coffee ring effect, plays a crucial role in phenomena as diverse as thin-film deposition, self-assembly, and biofilm formation. Recently, microorganisms have been shown to passively exploit and alter these deposition dynamics to increase their survival chances under harshening conditions. Here, we show that, as the droplet evaporation rate slows down, bacterial mobility starts playing a major role in determining the growth dynamics of the edge of drying droplets. Such motility-induced dynamics can influence several biophysical phenomena, from the formation of biofilms to the spreading of pathogens in humid environments and on surfaces subject to periodic drying. Analogous dynamics in other active matter systems can be exploited for technological applications in printing, coating, and self-assembly, where the standard coffee-ring effect is often a nuisance.