Emerging principles of primary cilia dynamics in controlling tissue organization and function.

Primary cilia project from the surface of most vertebrate cells and are key in sensing extracellular signals and locally transducing this information into a cellular response. Recent findings show that primary cilia are not merely static organelles with a distinct lipid and protein composition. Instead, the function of primary cilia relies on the dynamic composition of molecules within the cilium, the context-dependent sensing and processing of extracellular stimuli, and cycles of assembly and disassembly in a cell- and tissue-specific manner. Thereby, primary cilia dynamically integrate different cellular inputs and control cell fate and function during tissue development. Here, we review the recently emerging concept of primary cilia dynamics in tissue development, organization, remodeling, and function.

Mechanism of branching morphogenesis inspired by diatom silica formation.

The silica-based cell walls of diatoms are prime examples of genetically controlled, species-specific mineral architectures. The physical principles underlying morphogenesis of their hierarchically structured silica patterns are not understood, yet such insight could indicate novel routes toward synthesizing functional inorganic materials. Recent advances in imaging nascent diatom silica allow rationalizing possible mechanisms of their pattern formation. Here, we combine theory and experiments on the model diatom Thalassiosira pseudonana to put forward a minimal model of branched rib patterns-a fundamental feature of the silica cell wall. We quantitatively recapitulate the time course of rib pattern morphogenesis by accounting for silica biochemistry with autocatalytic formation of diffusible silica precursors followed by conversion into solid silica. We propose that silica deposition releases an inhibitor that slows down up-stream precursor conversion, thereby implementing a self-replicating reaction-diffusion system different from a classical Turing mechanism. The proposed mechanism highlights the role of geometrical cues for guided self-organization, rationalizing the instructive role for the single initial pattern seed known as the primary silicification site. The mechanism of branching morphogenesis that we characterize here is possibly generic and may apply also in other biological systems.

The molecular basis for pore pattern morphogenesis in diatom silica.

Biomineral-forming organisms produce inorganic materials with complex, genetically encoded morphologies that are unmatched by current synthetic chemistry. It is poorly understood which genes are involved in biomineral morphogenesis and how the encoded proteins guide this process. We addressed these questions using diatoms, which are paradigms for the self-assembly of hierarchically meso- and macroporous silica under mild reaction conditions. Proteomics analysis of the intracellular organelle for silica biosynthesis led to the identification of new biomineralization proteins. Three of these, coined dAnk1-3, contain a common protein-protein interaction domain (ankyrin repeats), indicating a role in coordinating assembly of the silica biomineralization machinery. Knocking out individual dank genes led to aberrations in silica biogenesis that are consistent with liquid-liquid phase separation as underlying mechanism for pore pattern morphogenesis. Our work provides an unprecedented path for the synthesis of tailored mesoporous silica materials using synthetic biology.

Diagnostic delay in Hidradenitis suppurativa investigated using data from social media and from statutory health insurances.

BACKGROUND: The chronic inflammatory skin disease hidradenitis suppurativa (HS) leads to severe pain and reduced quality of life. Nonetheless, it often takes years until a correct diagnosis is made. In this analysis, disease-related experiences and pathways of patients with HS were investigated and compared with the physicians' perspective. METHODS: Public posts on forums and social media as well as results of a survey conducted among dermatologists and their patients on the actual medical care reality of HS in Germany were analysed. Furthermore, claims data from German health insurance companies were evaluated. RESULTS: Patients with HS suffer from a 43.3% reduction in working ability. Dermatology (26.5%) was the most frequently consulted specialty, with HS diagnosed predominantly in the inpatient setting (43.8%). Abscesses were described as the most frequent alternative diagnosis in HS patients (53.2%). Patient-reported changes of physicians in dermatology (34.1%) and surgery (42.4%) occurred predominantly within the specialty. Dermatology received most referrals from general practitioners (67.1%), but only 12.1% from surgeons. CONCLUSION: There is an urgent need to reduce the delay in diagnosis and the prolonged burden of disease in patients with HS. Therefore, awareness of the disease, its detection and treatment which goes beyond dermatology should be promoted, if possible as part of medical studies.

Sperm chemotaxis in marine species is optimal at physiological flow rates according theory of filament surfing.

Sperm of marine invertebrates have to find eggs cells in the ocean. Turbulent flows mix sperm and egg cells up to the millimeter scale; below this, active swimming and chemotaxis become important. Previous work addressed either turbulent mixing or chemotaxis in still water. Here, we present a general theory of sperm chemotaxis inside the smallest eddies of turbulent flow, where signaling molecules released by egg cells are spread into thin concentration filaments. Sperm cells 'surf' along these filaments towards the egg. External flows make filaments longer, but also thinner. These opposing effects set an optimal flow strength. The optimum predicted by our theory matches flow measurements in shallow coastal waters. Our theory quantitatively agrees with two previous fertilization experiments in Taylor-Couette chambers and provides a mechanistic understanding of these early experiments. 'Surfing along concentration filaments' could be a paradigm for navigation in complex environments in the presence of turbulent flow.

Correction: Quantification of nematic cell polarity in three-dimensional tissues.

[This corrects the article DOI: 10.1371/journal.pcbi.1008412.].

The burden of incontinence in a real-world data environment-insights from a digital patient companion.

INTRODUCTION AND HYPOTHESIS: Urinary incontinence (UI) has a potentially devastating effect on women's quality of life (QoL). Conservative treatment by means of pelvic floor muscle training is the first-choice treatment modality. Nowadays, this can be supported by digital apps like pelvina©-a digital health companion pelvic floor course. METHODS: Using pelvina©, UI symptoms and QoL are regularly examined through the questionnaires QUID and SF-6D. Subsequently, we analyzed the incidence and degree of UI and its impact on QoL in 293 users in a real-world environment. RESULTS: The 293 patients included in this study had a median age of 36 years and a median of two children. Patients were slightly to moderately affected by UI with a QUID of 6 (2-11, maximum 24). Age and number of children were independently associated with the incidence of UI with an adjusted odds ratio (aOR) of 1.06 (95% CI 1.01-1.12) and aOR of 1.86 (95% CI 1.12-3.08). The severity of UI strongly correlated with impairment of QoL (ρ = 0.866, P < 0.001). CONCLUSIONS: The use of real-world data generated by digital health solutions offers the opportunity to gain insight into the reality of patients' lives. In this article, we corroborate the known associations between number of children and UI as well as the great influence UI has on QoL. This study shows that, in the future, the use of digital apps can make an important contribution to scientific data acquisition and, for example, therapy monitoring.

Synchronization in cilia carpets and the Kuramoto model with local coupling: Breakup of global synchronization in the presence of noise.

Carpets of beating cilia represent a paradigmatic example of self-organized synchronization of noisy biological oscillators, characterized by traveling waves of cilia phase. We present a multi-scale model of a cilia carpet that comprises realistic hydrodynamic interactions between cilia computed for a chiral cilia beat pattern from unicellular Paramecium and active noise of the cilia beat. We demonstrate an abrupt loss of global synchronization beyond a characteristic noise strength. We characterize stochastic transitions between synchronized and disordered dynamics, which generalize the notion of phase slips in pairs of coupled noisy phase oscillators. Our theoretical work establishes a link between the two-dimensional Kuramoto model of phase oscillators with mirror-symmetric oscillator coupling and detailed models of biological oscillators with asymmetric, chiral interactions.

Resilience of three-dimensional sinusoidal networks in liver tissue.

Can three-dimensional, microvasculature networks still ensure blood supply if individual links fail? We address this question in the sinusoidal network, a plexus-like microvasculature network, which transports nutrient-rich blood to every hepatocyte in liver tissue, by building on recent advances in high-resolution imaging and digital reconstruction of adult mice liver tissue. We find that the topology of the three-dimensional sinusoidal network reflects its two design requirements of a space-filling network that connects all hepatocytes, while using shortest transport routes: sinusoidal networks are sub-graphs of the Delaunay graph of their set of branching points, and also contain the corresponding minimum spanning tree, both to good approximation. To overcome the spatial limitations of experimental samples and generate arbitrarily-sized networks, we developed a network generation algorithm that reproduces the statistical features of 0.3-mm-sized samples of sinusoidal networks, using multi-objective optimization for node degree and edge length distribution. Nematic order in these simulated networks implies anisotropic transport properties, characterized by an empirical linear relation between a nematic order parameter and the anisotropy of the permeability tensor. Under the assumption that all sinusoid tubes have a constant and equal flow resistance, we predict that the distribution of currents in the network is very inhomogeneous, with a small number of edges carrying a substantial part of the flow-a feature known for hierarchical networks, but unexpected for plexus-like networks. We quantify network resilience in terms of a permeability-at-risk, i.e., permeability as function of the fraction of removed edges. We find that sinusoidal networks are resilient to random removal of edges, but vulnerable to the removal of high-current edges. Our findings suggest the existence of a mechanism counteracting flow inhomogeneity to balance metabolic load on the liver.

Quantification of nematic cell polarity in three-dimensional tissues.

How epithelial cells coordinate their polarity to form functional tissues is an open question in cell biology. Here, we characterize a unique type of polarity found in liver tissue, nematic cell polarity, which is different from vectorial cell polarity in simple, sheet-like epithelia. We propose a conceptual and algorithmic framework to characterize complex patterns of polarity proteins on the surface of a cell in terms of a multipole expansion. To rigorously quantify previously observed tissue-level patterns of nematic cell polarity (Morales-Navarrete et al., eLife 2019), we introduce the concept of co-orientational order parameters, which generalize the known biaxial order parameters of the theory of liquid crystals. Applying these concepts to three-dimensional reconstructions of single cells from high-resolution imaging data of mouse liver tissue, we show that the axes of nematic cell polarity of hepatocytes exhibit local coordination and are aligned with the biaxially anisotropic sinusoidal network for blood transport. Our study characterizes liver tissue as a biological example of a biaxial liquid crystal. The general methodology developed here could be applied to other tissues and in-vitro organoids.

Endovascular stroke treatment using balloon guide catheters may reduce penumbral tissue damage and improve long-term outcome.

OBJECTIVES: During mechanical recanalization of large vessel occlusions (LVO), the use of proximal flow arrest with balloon guide catheters (BGC) was shown to be associated with better angiographic and even clinical outcome. The aim of the study was to analyze the impact of BGC use on microstructural alterations in the salvaged penumbra. METHODS: All patients who underwent mechanical recanalization of LVO of the anterior circulation were reviewed within a prospective stroke registry of a single comprehensive stroke center. Fifty-two patients received an admission CT perfusion together with post-interventional diffusion tensor imaging. Technical details such as BGC usage were correlated with microstructural integrity changes of the salvaged gray matter through the mean diffusivity (MD) index. Moderation analysis was performed to test the interaction of BGC on the correlation between angiographic and clinical outcomes. RESULTS: For all patients with complete reperfusion, microstructural integrity changes with lowered MD index were found within the salvaged penumbra for cases of non-BGC usage (mean - 0.02) compared to cases with BGC usage (0.01, p = 0.04). The importance of complete reperfusion for good clinical outcome is predominantly based on patients treated with BGC (effect 2.78, p = 0.01 vs. for non-BGC: 0.3, p = 0.71). CONCLUSIONS: The lowered MD index early after mechanical recanalization without BGC usage can be interpreted as microstructural ischemic damage of the salvaged penumbra. It was shown that achieving complete reperfusion in a setting of BGC usage with proximal flow arrest minimizes penumbral damage and improves long-term outcomes. KEY POINTS: • Microstructural ischemic damage can be reduced by using proximal flow arrest during endovascular treatment with balloon guide catheter. • Complete reperfusion in a setting of balloon guide catheter minimizes penumbral damage and improves long-term outcome.

The "Flying Intervention Team": A Novel Stroke Care Concept for Rural Areas.

BACKGROUND: Endovascular treatment of large vessel occlusion in acute ischemic stroke patients is difficult to establish in remote areas, and time dependency of treatment effect increases the urge to develop health care concepts for this population. SUMMARY: Current strategies include direct transportation of patients to a comprehensive stroke center (CSC) ("mothership model") or transportation to the nearest primary stroke center (PSC) and secondary transfer to the CSC ("drip-and-ship model"). Both have disadvantages. We propose the model "flying intervention team." Patients will be transported to the nearest PSC; if telemedically identified as eligible for thrombectomy, an intervention team will be acutely transported via helicopter to the PSC and endovascular treatment will be performed on site. Patients stay at the PSC for further stroke unit care. This model was implemented at a telestroke network in Germany. Fifteen remote hospitals participated in the project, covering 14,000 km2 and a population of 2 million. All have well established telemedically supported stroke units, an angiography suite, and a helicopter pad. Processes were defined individually for each hospital and training sessions were implemented for all stroke teams. An exclusive project helicopter was installed to be available from 8 a.m. to 10 p.m. during 26 weeks per year. Key Messages: The model of the flying intervention team is likely to reduce time delays since processes will be performed in parallel, rather than consecutively, and since it is quicker to move a medical team rather than a patient. This project is currently under evaluation (clinicaltrials NCT04270513).

Lagrangian mechanics of active systems.

We present a multi-scale modeling and simulation framework for low-Reynolds number hydrodynamics of shape-changing immersed objects, e.g., biological microswimmers and active surfaces. The key idea is to consider principal shape changes as generalized coordinates and define conjugate generalized hydrodynamic friction forces. Conveniently, the corresponding generalized friction coefficients can be pre-computed and subsequently reused to solve dynamic equations of motion fast. This framework extends Lagrangian mechanics of dissipative systems to active surfaces and active microswimmers, whose shape dynamics is driven by internal forces. As an application case, we predict in-phase and anti-phase synchronization in pairs of cilia for an experimentally measured cilia beat pattern.

Micromotor-mediated sperm constrictions for improved swimming performance.

Sperm-driven micromotors, consisting of a single sperm cell captured in a microcap, utilize the strong propulsion generated by the flagellar beat of motile spermatozoa for locomotion. It enables the movement of such micromotors in biological media, while being steered remotely by means of an external magnetic field. The substantial decrease in swimming speed, caused by the additional hydrodynamic load of the microcap, limits the applicability of sperm-based micromotors. Therefore, to improve the performance of such micromotors, we first investigate the effects of additional cargo on the flagellar beat of spermatozoa. We designed two different kinds of microcaps, which each result in different load responses of the flagellar beat. As an additional design feature, we constrain rotational degrees of freedom of the cell's motion by modifying the inner cavity of the cap. Particularly, cell rolling is substantially reduced by tightly locking the sperm head inside the microcap. Likewise, cell yawing is decreased by aligning the micromotors under an external static magnetic field. The observed differences in swimming speed of different micromotors are not so much a direct consequence of hydrodynamic effects, but rather stem from changes in flagellar bending waves, hence are an indirect effect. Our work serves as proof-of-principle that the optimal design of microcaps is key for the development of efficient sperm-driven micromotors.

Structured reporting of brain MRI following mechanical thrombectomy in acute ischemic stroke patients.

BACKGROUND: To compare the quality of free-text reports (FTR) and structured reports (SR) of brain magnetic resonance imaging (MRI) examinations in patients following mechanical thrombectomy for acute stroke treatment. METHODS: A template for SR of brain MRI examinations based on decision trees was designed and developed in house and applied to twenty patients with acute ischemic stroke in addition to FTR. Two experienced stroke neurologists independently evaluated the quality of FTR and SR regarding clarity, content, presence of key features, information extraction, and overall report quality. The statistical analysis for the differences between FTR and SR was performed using the Mann-Whitney U-test or the Chi-squared test. RESULTS: Clarity (p < 0.001), comprehensibility (p < 0.001), inclusion of relevant findings (p = 0.016), structure (p = 0.005), and satisfaction with the content of the report for immediate patient management (p < 0.001) were evaluated significantly superior for the SR by both neurologist raters. One rater additionally found the explanation of the patient's clinical symptoms (p = 0.003), completeness (p < 0.009) and length (p < 0.001) of SR to be significantly superior compared to FTR and stated that there remained no open questions, requiring further consultation of the radiologist (p < 0.001). Both neurologists preferred SR over FTR. CONCLUSIONS: The use of SR for brain magnetic resonance imaging may increase the report quality and satisfaction of the referring physicians in acute ischemic stroke patients following mechanical thrombectomy. Trial registration Retrospectively registered.

From Perviousness to Plaque Imaging in Acute Basilar Occlusions: The Impact of Underlying Stenosis and How to Detect It.

Background and Purpose- Recent studies show that mechanical thrombectomy of acute basilar artery occlusions (BAO) results in high rates of successful recanalization and good outcomes, but predictors are not completely established yet. Varying occlusion types may benefit differently, and especially, an underlying basilar stenosis (BS) seems to have an impact. Aim of this study was to investigate angiographic and clinical differences in BAO subtypes and to test the potential of perviousness measures for a preinterventional identification of clinically relevant different occlusion types. Methods- All consecutive patients with acute BAO, endovascular treated at a single comprehensive stroke center, were included. Different occlusion patterns, especially underlying BS, were identified and analyzed in respect of angiographic and clinical (National Institutes of Health Stroke Scale/modified Rankin Scale) outcome parameters (N=115). Thrombus perviousness measures (change in thrombus attenuation Δt and corrected void fraction ε) were assessed in admission computed tomography imaging and correlated to different etiological subgroups. Results- Despite comparable rates of successful recanalization (87% for BAO with BS versus 95% without BS), the BS group showed worse clinical outcome with higher National Institutes of Health Stroke Scale/modified Rankin Scale values (P=0.002/0.003). The group of BS turned out to have lower thrombus density values in unenhanced scans (mean, 42.0 Hounsfield units) and higher perviousness measures Δt (mean, 34.6 Hounsfield units) and ε (mean, 0.23) than thrombi without an underlying BS (mean, 53.6 Hounsfield units/13.1 Hounsfield units/0.08, P=0.01/ 0.004/ 0.001). Conclusions- In agreement with previous studies, outcome of mechanical thrombectomy of BAO seems to depend on pathogenesis with less clinical benefit for underlying BS, raising the question of early identification of this subgroup. Perviousness showed a high potential to differentiate acute BAO with and without BS, possibly usable as an admission imaging marker for BS.

Sperm-Driven Micromotors Moving in Oviduct Fluid and Viscoelastic Media.

Biohybrid micromotors propelled by motile cells are fascinating entities for autonomous biomedical operations on the microscale. Their operation under physiological conditions, including highly viscous environments, is an essential prerequisite to be translated to in vivo settings. In this work, a sperm-driven microswimmer, referred to as a spermbot, is demonstrated to operate in oviduct fluid in vitro. The viscoelastic properties of bovine oviduct fluid (BOF), one of the fluids that sperm cells encounter on their way to the oocyte, are first characterized using passive microrheology. This allows to design an artificial oviduct fluid to match the rheological properties of oviduct fluid for further experiments. Sperm motion is analyzed and it is confirmed that kinetic parameters match in real and artificial oviduct fluids, respectively. It is demonstrated that sperm cells can efficiently couple to magnetic microtubes and propel them forward in media of different viscosities and in BOF. The flagellar beat pattern of coupled as well as of free sperm cells is investigated, revealing an alteration on the regular flagellar beat, presenting an on-off behavior caused by the additional load of the microtube. Finally, a new microcap design is proposed to improve the overall performance of the spermbot in complex biofluids.

Chemokinetic Scattering, Trapping, and Avoidance of Active Brownian Particles.

We present a theory of chemokinetic search agents that regulate directional fluctuations according to distance from a target. A dynamic scattering effect reduces the probability to penetrate regions with high fluctuations and thus reduces search success for agents that respond instantaneously to positional cues. In contrast, agents with internal states that initially suppress chemokinesis can exploit scattering to increase their probability to find the target. Using matched asymptotics between the case of diffusive and ballistic search, we obtain analytic results beyond Fox colored noise approximation.

Mechanical Thrombectomy of the Middle Cerebral Artery - Neither Segment nor Diameter Matter.

OBJECTIVES: The aim of this study was to explore the role of the vessel diameter at the site of middle cerebral artery (MCA) occlusion in acute ischemic stroke patients who underwent mechanical thrombectomy (MT) regarding technical aspects, safety, and clinical outcomes. METHODS: In a retrospective analysis, cerebral artery diameters were measured using digital subtraction angiography in patients with isolated M1 or M2 occlusions undergoing MT. Associations between occluded vessel, occlusion diameter and outcomes were analyzed using logistic regression models adjusting for prespecified prognostic factors. RESULTS: 168 patients with M1 occlusions and 98 patients with M2 occlusions who underwent MT were included. Mean vessel diameters at M1 and M2 occlusion sites differed significantly (2.15 +/- .36 1.55 +/- .38, P < .001). Vessel diameters at the occlusion site and occluded vessel segment did not predict good functional outcome (aOR 1.2 CI .28-5.26, P = .659; aOR .84 CI .35-2.03, P = .841) or mortality (aOR .21 CI .04-1.01, P = .215; aOR 1.36 CI .55-3.37, P = .676). No significant differences in successful recanalization, good functional outcome, mortality, procedural complications, and intracranial hemorrhages between M1 and M2 occlusions was observed. CONCLUSIONS: In this study no significant effect of the MCA vessel diameter on successful recanalization, good functional outcome, or mortality of acute ischemic stroke patients treated with MT could be detected. However, these findings need to be confirmed in further studies.

Impact of brain volume and intracranial cerebrospinal fluid volume on the clinical outcome in endovascularly treated stroke patients.

PURPOSE: Previously, brain volume (BV) and intracranial cerebrospinal fluid volume (CSFV) have been investigated regarding clinical outcomes of subgroups of ischemic stroke patients. This study aimed to examine if the preexisting, preischemic BV and CSFV have an impact on good functional outcome and mortality in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). METHODS: Preischemic BV, CSFV, and CSFV/Total intracranial volume (TICV)-ratio were calculated with a fully automated segmentation platform. Univariate and multivariate analyses were used to study associations. RESULTS: In this retrospective study 107 subsequent AIS patients of a prospective database were included. The segmentation results of the fully automated algorithm based on non-contrast computerized tomography scans (NCCT) correlated significantly with the segmentation results obtained from 3D T1 weighted magnetic resonance images (P < 0.001). In the univariate analysis a preexisting BV (P < 0.001), preexisting CSFV (P = 0.009), and the ratio CSFV/total intracranial volume (P < 0.001) each significantly correlated with good functional outcome and mortality. However, in the multivariate regression analysis, also correcting for patient age, none of these volumes remained to correlate with these outcome parameters. CONCLUSION: In summary, an association of BV, CSFV, and the CSFV/TICV-ratio with good functional outcome and mortality in AIS treated with MT could not be established. A fully automated segmentation algorithm based on NCCT was successfully developed in-house for calculating the volumes of interest.