Novel molecular, structural and clinical findings in an Italian cohort of congenital cataract.

The current genetic diagnostic workup of congenital cataract (CC) is mainly based on NGS panels, whereas exome sequencing (ES) has occasionally been employed. In this multicentre study, we investigated by ES the detection yield, mutational spectrum and genotype-phenotype correlations in a CC cohort recruited between 2020 and mid-2022. The cohort consisted of 67 affected individuals from 51 unrelated families and included both non-syndromic (75%) and syndromic (25%) phenotypes, with extra-CC ocular/visual features present in both groups (48% and 76%, respectively). The functional effect of variants was predicted by 3D modelling and hydropathy properties changes. Variant clustering was used for the in-depth assessment of genotype-phenotype correlations. A diagnostic (pathogenic or likely pathogenic) variant was identified in 19 out of 51 probands/families (~37%). In a further 14 probands/families a candidate variant was identified: in 12 families a VUS was detected, of which 9 were considered plausibly pathogenic (i.e., 4 or 5 points according to ACMG criteria), while in 2 probands ES identified a single variant in an autosomal recessive gene associated with CC. Eighteen probands/families, manifesting primarily non-syndromic CC (15/18, 83%), remained unsolved. The identified variants (8 P, 12 LP, 10 VUS-PP, and 5 VUS), half of which were unreported in the literature, affected five functional categories of genes involved in transcription/splicing, lens formation/homeostasis (i.e., crystallin genes), membrane signalling, cell-cell interaction, and immune response. A phenotype-specific variant clustering was observed in four genes (KIF1A, MAF, PAX6, SPTAN1), whereas variable expressivity and potential phenotypic expansion in two (BCOR, NHS) and five genes (CWC27, KIF1A, IFIH1, PAX6, SPTAN1), respectively. Finally, ES allowed to detect variants in six genes not commonly included in commercial CC panels. These findings broaden the genotype-phenotype correlations in one of the largest CC cohorts tested by ES, providing novel insights into the underlying pathogenetic mechanisms and emphasising the power of ES as first-tier test.

Emergent probability fluxes in confined microbial navigation.

When the motion of a motile cell is observed closely, it appears erratic, and yet the combination of nonequilibrium forces and surfaces can produce striking examples of organization in microbial systems. While most of our current understanding is based on bulk systems or idealized geometries, it remains elusive how and at which length scale self-organization emerges in complex geometries. Here, using experiments and analytical and numerical calculations, we study the motion of motile cells under controlled microfluidic conditions and demonstrate that probability flux loops organize active motion, even at the level of a single cell exploring an isolated compartment of nontrivial geometry. By accounting for the interplay of activity and interfacial forces, we find that the boundary's curvature determines the nonequilibrium probability fluxes of the motion. We theoretically predict a universal relation between fluxes and global geometric properties that is directly confirmed by experiments. Our findings open the possibility to decipher the most probable trajectories of motile cells and may enable the design of geometries guiding their time-averaged motion.

Active Spaghetti: Collective Organization in Cyanobacteria.

Filamentous cyanobacteria can show fascinating examples of nonequilibrium self-organization, which, however, are not well understood from a physical perspective. We investigate the motility and collective organization of colonies of these simple multicellular lifeforms. As their area density increases, linear chains of cells gliding on a substrate show a transition from an isotropic distribution to bundles of filaments arranged in a reticulate pattern. Based on our experimental observations of individual behavior and pairwise interactions, we introduce a nonreciprocal model accounting for the filaments' large aspect ratio, fluctuations in curvature, motility, and nematic interactions. This minimal model of active filaments recapitulates the observations, and rationalizes the appearance of a characteristic length scale in the system, based on the Péclet number of the cyanobacteria filaments.

Congenital isolated unilateral third nerve palsy in children: the diagnostic contribution of high-resolution MR imaging.

PURPOSE: To describe the neuroanatomical correlates of unilateral congenital isolated oculomotor palsy by means of high-resolution MRI. METHODS: Children with a clinical diagnosis of congenital isolated oculomotr palsy and with a high-resolution MRI acquisition targeted on the orbits and cranial nerves were selected and included in the study. An experienced pediatric neuroradiologist evaluated all the exams, assessing the integrity and morphology of extraocular muscles, oculomotor, trochlear and abducens nerves as well as optic nerves and globes. Clinical data and ophthalmologic evaluations were also collected. RESULTS: Six children (age range: 1-16 years; males: 3) were selected. All patients showed, on the affected side (left:right = 5:1), anomalies of the III nerve and extraocular muscles innervated by the pathological nerve. One patient had complete nerve agenesis, two patients showed a diffuse thinning of the nerve, from the brainstem to the orbit and 3 patients showed a distal thinning of the oculomotor nerve, starting at the level of the cavernous sinus. In all cases atrophy of corresponding muscles was noticed, but the involvement of the affected muscles varied with the nervous pattern of injury. CONCLUSIONS: High-resolution MRI represents a valuable tool for the diagnosis of III nerve anomalies in unilateral congenital IOP, showing different patterns of nerve involvement and muscular atrophy.

Multiparticle collision dynamics simulations of a squirmer in a nematic fluid.

We study the dynamics of a squirmer in a nematic liquid crystal using the multiparticle collision dynamics (MPCD) method. A recently developed nematic MPCD method [Phys. Rev. E 99, 063319 (2019)] which employs a tensor order parameter to describe the spatial and temporal variations of the nematic order is used to simulate the suspending anisotropic fluid. Considering both nematodynamic effects (anisotropic viscosity and elasticity) and thermal fluctuations, in the present study, we couple the nematic MPCD algorithm with a molecular dynamics (MD) scheme for the squirmer. A unique feature of the proposed method is that the nematic order, the fluid, and the squirmer are all represented in a particle-based framework. To test the applicability of this nematic MPCD-MD method, we simulate the dynamics of a spherical squirmer with homeotropic surface anchoring conditions in a bulk domain. The importance of anisotropic viscosity and elasticity on the squirmer's speed and orientation is studied for different values of self-propulsion strength and squirmer type (pusher, puller or neutral). In sharp contrast to Newtonian fluids, the speed of the squirmer in a nematic fluid depends on the squirmer type. Interestingly, the speed of a strong pusher is smaller in the nematic fluid than for the Newtonian case. The orientational dynamics of the squirmer in the nematic fluid also shows a non-trivial dependence on the squirmer type. Our results compare well with existing experimental and numerical data. The full particle-based framework could be easily extended to model the dynamics of multiple squirmers in anisotropic fluids.

Flow-assisted self-healing of the helical structure in a cholesteric liquid crystal.

We employ nonequilibrium molecular dynamics simulations to investigate the structure and dynamics of a cholesteric liquid crystal confined between atomically corrugated solid walls. By choosing walls normal to the helical axis, we can study systems with an arbitrary cholesteric pitch without exposing the cholesteric helix to a spurious stress. We investigate the effects of local heating and flow and their joint effects. A steady-state laminar Poiseuille flow is initiated by means of an external body force. Flow alone (i.e., without local heating) in a direction normal to the helical axis does not affect the cholesteric pitch. If the liquid crystal is heated in a small region, the cholesteric helix becomes unstable and melts locally. However, if local heating and flow are combined, a nontrivial synergistic effect is observed in that the helical structure recuperates the better, the higher the speed of the flow is.

Emergence of phytoplankton patchiness at small scales in mild turbulence.

Phytoplankton often encounter turbulence in their habitat. As most toxic phytoplankton species are motile, resolving the interplay of motility and turbulence has fundamental repercussions on our understanding of their own ecology and of the entire ecosystems they inhabit. The spatial distribution of motile phytoplankton cells exhibits patchiness at distances of decimeter to millimeter scales for numerous species with different motility strategies. The explanation of this general phenomenon remains challenging. Furthermore, hydrodynamic cell-cell interactions, which grow more relevant as the density in the patches increases, have been so far ignored. Here, we combine particle simulations and continuum theory to study the emergence of patchiness in motile microorganisms in three dimensions. By addressing the combined effects of motility, cell-cell interaction, and turbulent flow conditions, we uncover a general mechanism: The coupling of cell-cell interactions to the turbulent dynamics favors the formation of dense patches. Identification of the important length and time scales, independent from the motility mode, allows us to elucidate a general physical mechanism underpinning the emergence of patchiness. Our results shed light on the dynamical characteristics necessary for the formation of patchiness and complement current efforts to unravel planktonic ecological interactions.

Dynamics of sedimenting active Brownian particles.

We investigate the stochastic dynamics of one sedimenting active Brownian particle in three dimensions under the influence of gravity and passive fluctuations in the translational and rotational motion. We present an analytical solution of the Fokker-Planck equation for the stochastic process which allows us to describe the dynamics of one active Brownian particle in three dimensions. We address the time evolution of the density, the polarization, and the steady-state solution. We also perform Brownian dynamics simulations and study the effect of the activity of the particles on their collective motion. These results qualitatively agree with our model. Finally, we compare our results with experiments (J. Palacci et al., Phys. Rev. Lett. 105, 088304 (2010)) and find very good agreement.

Hydrodynamic interactions dominate the structure of active swimmers' pair distribution functions.

Microswimmers often exhibit surprising patterns due to the nonequilibrium nature of their dynamics. Collectively, suspensions of microswimmers appear as a liquid whose properties set it apart from its passive counterpart. To understand the impact of hydrodynamic interactions on the basic statistical features of a microswimmer's liquid, we investigate its structure by means of the pair distribution function. We perform particle-based simulations of microswimmers that include steric effects, shape anisotropy, and hydrodynamic interactions. We find that hydrodynamic interactions considerably alter the orientation-dependent pair distribution function compared to purely excluded-volume models like active Brownian particles and generally decrease the structure of the liquid. Depletion regions are dominant at lower filling fractions, while at larger filling fraction, the microswimmer liquid develops a stronger first shell of neighbors in specific directions, while losing structure at larger distances. Our work is a first step toward a statistico-mechanical treatment of the structure of microswimmer suspensions.

Curvature-Guided Motility of Microalgae in Geometric Confinement.

Microorganisms, such as bacteria and microalgae, often live in habitats consisting of a liquid phase and a plethora of interfaces. The precise ways in which these motile microbes behave in their confined environment remain unclear. Using experiments and Brownian dynamics simulations, we study the motility of a single Chlamydomonas microalga in an isolated microhabitat with controlled geometric properties. We demonstrate how the geometry of the habitat controls the cell's navigation in confinement. The probability of finding the cell swimming near the boundary increases with the wall curvature, as seen for both circular and elliptical chambers. The theory, utilizing an asymmetric dumbbell model of the cell and steric wall interactions, captures this curvature-guided navigation quantitatively with no free parameters.

Quantized Self-Assembly of Discotic Rings in a Liquid Crystal Confined in Nanopores.

Disklike molecules with aromatic cores spontaneously stack up in linear columns with high, one-dimensional charge carrier mobilities along the columnar axes, making them prominent model systems for functional, self-organized matter. We show by high-resolution optical birefringence and synchrotron-based x-ray diffraction that confining a thermotropic discotic liquid crystal in cylindrical nanopores induces a quantized formation of annular layers consisting of concentric circular bent columns, unknown in the bulk state. Starting from the walls this ring self-assembly propagates layer by layer towards the pore center in the supercooled domain of the bulk isotropic-columnar transition and thus allows one to switch on and off reversibly single, nanosized rings through small temperature variations. By establishing a Gibbs free energy phase diagram we trace the phase transition quantization to the discreteness of the layers' excess bend deformation energies in comparison to the thermal energy, even for this near room-temperature system. Monte Carlo simulations yielding spatially resolved nematic order parameters, density maps, and bond-orientational order parameters corroborate the universality and robustness of the confinement-induced columnar ring formation as well as its quantized nature.

Maximum in density heterogeneities of active swimmers.

Suspensions of unicellular microswimmers such as flagellated bacteria or motile algae can exhibit spontaneous density heterogeneities at large enough concentrations. We introduce a novel model for biological microswimmers that creates the flow field of the corresponding microswimmers, and takes into account the shape anisotropy of the swimmer's body and stroke-averaged flagella. By employing multiparticle collision dynamics, we directly couple the swimmer's dynamics to the fluid's. We characterize the nonequilibrium phase diagram, as the filling fraction and Péclet number are varied, and find density heterogeneities in the distribution of both pullers and pushers, due to hydrodynamic instabilities. We find a maximum degree of clustering at intermediate filling fractions and at large Péclet numbers resulting from a competition of hydrodynamic and steric interactions between the swimmers. We develop an analytical theory that supports these results. This maximum might represent an optimum for the microorganisms' colonization of their environment.

Clinical evaluation and molecular screening of a large consecutive series of albino patients.

Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. In this study we recruited 321 albino patients and screened them for the genes known to cause oculocutaneous albinism (OCA1-4 and OCA6) and ocular albinism (OA1). Our purpose was to detect mutations and genetic frequencies of the main causative genes, offering to albino patients an exhaustive diagnostic assessment within a multidisciplinary approach including ophthalmological, dermatological, audiological and genetic evaluations. We report 70 novel mutations and the frequencies of the major causative OCA genes that are as follows: TYR (44%), OCA2 (17%), TYRP1 (1%), SLC45A2 (7%) and SLC24A5 (<0.5%). An additional 5% of patients had GPR143 mutations. In 19% of cases, a second reliable mutation was not detected, whereas 7% of our patients remain still molecularly undiagnosed. This comprehensive study of a consecutive series of OCA/OA1 patients allowed us to perform a clinical evaluation of the different OCA forms.

The Impact of Colloidal Surface-Anchoring on the Smectic A Phase.

Liquid-crystalline phases are known for their unique properties, i.e., the combination of fluidity and long-range orientational and/or positional order. The presence of a colloidal particle gives rise to perturbations of this order locally. These perturbations are the origin of intercolloidal forces driving the colloidal self-assembly in a directed manner. Hence, the understanding of these perturbations is the first step in understanding and controlling the self-assembly process. Here, we perform Monte Carlo simulations to investigate the perturbations of orientational and positional order in a smectic A phase caused by a spherical colloid. We model the host phase via an interaction potential that reproduces characteristic features of phase behavior, structure, dynamics, and elasticity [S. Püschel-Schlotthauer et al. J. Chem. Phys. 2016, 145, 164903]. For strong homeotropic anchoring conditions, we find a Saturn ring defect and an onion structure in the smectic A phase; the latter has never been reported for colloids so far. For strong planar anchoring conditions, we find Boojum defects that become elongated at low temperature, similar to what is observed in experiments. However, for weak planar anchoring conditions, a double surface ring defect is exhibited in the smectic A phase.

Coarse-grained treatment of the self-assembly of colloids suspended in a nematic host phase.

The complex interplay of molecular scale effects, nonlinearities in the orientational field and long-range elastic forces makes liquid-crystal physics very challenging. A consistent way to extract information from the microscopic, molecular scale up to the meso- and macroscopic scale is still missing. Here, we develop a hybrid procedure that bridges this gap by combining extensive Monte Carlo (MC) simulations, a local Landau-de Gennes theory, classical density functional theory, and finite-size scaling theory. As a test case to demonstrate the power and validity of our novel approach we study the effective interaction among colloids with Boojum defect topology immersed in a nematic liquid crystal. In particular, at sufficiently small separations colloids attract each other if the angle between their center-of-mass distance vector and the far-field nematic director is about 30°. Using the effective potential in coarse-grained two-dimensional MC simulations we show that self-assembled structures formed by the colloids are in excellent agreement with experimental data.

A novel model for smectic liquid crystals: Elastic anisotropy and response to a steady-state flow.

By means of a combination of equilibrium Monte Carlo and molecular dynamics simulations and nonequilibrium molecular dynamics we investigate the ordered, uniaxial phases (i.e., nematic and smectic A) of a model liquid crystal. We characterize equilibrium behavior through their diffusive behavior and elastic properties. As one approaches the equilibrium isotropic-nematic phase transition, diffusion becomes anisotropic in that self-diffusion D⊥ in the direction orthogonal to a molecule's long axis is more hindered than self-diffusion D∥ in the direction parallel to that axis. Close to nematic-smectic A phase transition the opposite is true, D∥ < D⊥. The Frank elastic constants K1, K2, and K3 for the respective splay, twist, and bend deformations of the director field n̂ are no longer equal and exhibit a temperature dependence observed experimentally for cyanobiphenyls. Under nonequilibrium conditions, a pressure gradient applied to the smectic A phase generates Poiseuille-like or plug flow depending on whether the convective velocity is parallel or orthogonal to the plane of smectic layers. We find that in Poiseuille-like flow the viscosity of the smectic A phase is higher than in plug flow. This can be rationalized via the velocity-field component in the direction of the flow. In a sufficiently strong flow these smectic layers are not destroyed but significantly bent.

Stochastic rotation dynamics for nematic liquid crystals.

We introduce a new mesoscopic model for nematic liquid crystals (LCs). We extend the particle-based stochastic rotation dynamics method, which reproduces the Navier-Stokes equation, to anisotropic fluids by including a simplified Ericksen-Leslie formulation of nematodynamics. We verify the applicability of this hybrid model by studying the equilibrium isotropic-nematic phase transition and nonequilibrium problems, such as the dynamics of topological defects and the rheology of sheared LCs. Our simulation results show that this hybrid model captures many essential aspects of LC physics at the mesoscopic scale, while preserving microscopic thermal fluctuations.

Effects of flow on topological defects in a nematic liquid crystal near a colloid.

We perform molecular dynamics simulations of a nematic liquid crystal flowing around a colloidal particle. We study the flow-induced modifications of the topological defects in the liquid crystal due to the presence of the colloid. We show that flow distorts Boojum defects into an asymmetrically larger downstream lobe, and that Saturn ring defects are convected downstream along the flow direction, which is in agreement with experimental observations. Additionally, for a Janus colloid with both parallel and perpendicular patches, exhibiting a Boojum defect and a Saturn ring defect, we find that the Boojum defect facing the upstream direction is destroyed and the Saturn ring is convected downstream.

More than one dynamic crossover in protein hydration water.

Studies of liquid water in its supercooled region have helped us better understand the structure and behavior of water. Bulk water freezes at its homogeneous nucleation temperature (approximately 235 K), but protein hydration water avoids this crystallization because each water molecule binds to a protein. Here, we study the dynamics of the hydrogen bond (HB) network of a percolating layer of water molecules and compare the measurements of a hydrated globular protein with the results of a coarse-grained model that successfully reproduces the properties of hydration water. Using dielectric spectroscopy, we measure the temperature dependence of the relaxation time of proton charge fluctuations. These fluctuations are associated with the dynamics of the HB network of water molecules adsorbed on the protein surface. Using Monte Carlo simulations and mean-field calculations, we study the dynamics and thermodynamics of the model. Both experimental and model analyses are consistent with the interesting possibility of two dynamic crossovers, (i) at approximately 252 K and (ii) at approximately 181 K. Because the experiments agree with the model, we can relate the two crossovers to the presence at ambient pressure of two specific heat maxima. The first is caused by fluctuations in the HB formation, and the second, at a lower temperature, is due to the cooperative reordering of the HB network.