Geometric control of active flows

The development of an organism starting from a fertilized egg involves the self-organized formation of patterns and the generation of shape. Patterns and shapes are characterized by their geometry, i.e. angles and distances between features. In this thesis, we set out to understand how the given geometry of pattern and shape of a living system feeds back into the evolution of this geometry. We focus on two fundamental developmental processes: axis specification and gastrulation. Both processes rely on the directed movements of cells and molecules driven by molecular force generation. Here, we ask how the geometry of an embryo guides such active flows. Active flows are often confined to the surface of a cell or embryo which is usually curved. We use the hydrodynamic theory of active surfaces to investigate how this curvature impacts on flows that are driven by patterns of mechanical activity. Using a minimal model of the cell cortex, we find that active cortical stresses can drive a rotation of the cell that aligns the chemical pattern of the stress regulator with the geometry of the cell surface. In particular, we find that active tension in the cytokinetic ring ensures that a cell divides along its longest axes, a common phenomenon known as Hertwig’s rule. As a consequence, the body axes of the C. elegans embryo are aligned with the geometry of the egg shell. We next set out to understand the impact of surface geometry on flows and patterns in more complex geometries. We focus in particular on localized sources of mechanical activity in curved fluid films. Such active particles act as sensors of the surface geometry, as the viscosity relates the local flow field to the large-scale geometry of the fluid film. We find that the impact of an anisotropic surface geometry on the flow field can generally be understood in terms of effective gradients of friction and viscosity. With this, we show that contractile points in a fluid film are attracted by protrusions and saddle geometries where the contractile point is surrounded by a maximal amount of surface area within the hydrodynamic length. Furthermore, we find that anisotropic active particles move towards or away from a saddle of the surface depending on whether they are extensile or contractile. To understand the process of gastrulation and left-right symmetry breaking in the avian embryo, we develop a hydrodynamic theory of the primitive streak, a line of mechanically active material. With this theory of an active viscous crack, we analyze experimental data from quail embryos. We find that the embryo-scale cell movements during gastrulation are driven by mechanical activity at the streak, while the surrounding epithelium behaves like a homogeneous fluid film. With this mechanical model, we find that streak elongation does not require extensile forces along the streak. Instead, streak elongation results from the flux of tissue into the streak, the viscosity of the surrounding tissue and the polar geometry of the streak. During avian left-right symmetry breaking, a chiral flow of tissue emerges at the tip of the streak, the so called Hensen’s node. We find that this flow results from an active torque that drives a counter-rotation of tissue layers. Thus, avian left-right symmetry breaking is facilitated by the mechanical coupling of tissue layers that the structure of node and streak provides. Finally, we study how the geometry of a surface impacts on such chiral flows. We find that chiral flows at the avian node as well as in the cell cortex can be recapitulated as the result of molecular torque dipoles that are aligned with the tangential plane of the cell or tissue surface. Only when the surface is curved, such in-plane torques drive in-plane flows. Thus, the geometry of the avian node and the cytokinetic furrow may facilitate the chiral flows that are driven by these structures. Taken together, we find that the geometry of an embryo is crucial to the flows and patterns that emerge in such a mechanically active system, because the geometry defines how forces and torques are transmitted.:1 Introduction 1.1 Embryogenesis from a geometric viewpoint 1.2 Hydrodynamic theory of active fluid films 1.3 Understanding active surfaces with complex numbers 1.4 Overview of this thesis 2 Crack mechanics of avian gastrulation 2.1 The primitive streak as a crack in a fluid film 2.2 Hydrodynamic theory of active viscous cracks 2.3 The primitive streak as a branch cut 2.4 Advective crack propagation 2.5 Discussion 3 Pattern formation guided by surface geometry 3.1 Minimal model of guided symmetry breaking 3.2 Diffusion on a curved surface 3.3 Pattern formation in an active fluid model of the cell cortex 3.4 Discussion 4 Geometry sensing by active flows 4.1 Geometry sensing by an active isotropic fluid 4.2 Deformation response of active flow in general surface geometries 4.3 Geometry sensing by a contractile point 4.4 Pattern formation guided by the geometric potential 4.5 Geometry sensing by active p-atic particles 4.6 Discussion 5 Chiral flows controlled by embryo geometry 5.1 Mechanical model of avian left-right symmetry breaking 5.2 Chiral flows facilitated by curvature gradients 5.3 Discussion 6 Conclusion and Outloo

Power-Law Population Heterogeneity Governs Epidemic Waves

We generalize the Susceptible-Infected-Removed model for epidemics to take into account generic effects of heterogeneity in the degree of susceptibility to infection in the population. We introduce a single new parameter corresponding to a power-law exponent of the susceptibility distribution that characterizes the population heterogeneity. We show that our generalized model is as simple as the original model which is contained as a limiting case. Because of this simplicity, numerical solutions can be generated easily and key properties of the epidemic wave can still be obtained exactly. In particular, we present exact expressions for the herd immunity level, the final size of the epidemic, as well as for the shape of the wave and for observables that can be quantified during an epidemic. We find that in strongly heterogeneous populations the epidemic reaches only a small fraction of the population. This implies that the herd immunity level can be much lower than in commonly used models with homogeneous populations. Using our model to analyze data for the SARS-CoV-2 epidemic in Germany shows that the reported time course is consistent with several scenarios characterized by different levels of immunity. These scenarios differ in population heterogeneity and in the time course of the infection rate, for example due to mitigation efforts or seasonality. Our analysis reveals that quantifying the effects of mitigation requires knowledge on the degree of heterogeneity in the population. Our work shows that key effects of population heterogeneity can be captured without increasing the complexity of the model. We show that information about population heterogeneity will be key to understand how far an epidemic has progressed and what can be expected for its future course.Comment: 34 pages, 8 figure

Power-law population heterogeneity governs epidemic waves

We generalize the Susceptible-Infected-Removed (SIR) model for epidemics to take into account generic effects of heterogeneity in the degree of susceptibility to infection in the population. We introduce a single new parameter corresponding to a power-law exponent of the susceptibility distribution at small susceptibilities. We find that for this class of distributions the gamma distribution is the attractor of the dynamics. This allows us to identify generic effects of population heterogeneity in a model as simple as the original SIR model which is contained as a limiting case. Because of this simplicity, numerical solutions can be generated easily and key properties of the epidemic wave can still be obtained exactly. In particular, we present exact expressions for the herd immunity level, the final size of the epidemic, as well as for the shape of the wave and for observables that can be quantified during an epidemic. In strongly heterogeneous populations, the herd immunity level can be much lower than in models with homogeneous populations as commonly used for example to discuss effects of mitigation. Using our model to analyze data for the SARS-CoV-2 epidemic in Germany shows that the reported time course is consistent with several scenarios characterized by different levels of immunity. These scenarios differ in population heterogeneity and in the time course of the infection rate, for example due to mitigation efforts or seasonality. Our analysis reveals that quantifying the effects of mitigation requires knowledge on the degree of heterogeneity in the population. Our work shows that key effects of population heterogeneity can be captured without increasing the complexity of the model. We show that information about population heterogeneity will be key to understand how far an epidemic has progressed and what can be expected for its future course

Dendritic cells: Key players in human herpesvirus 8 infection and pathogenesis

Human herpesvirus 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) is an oncogenic gammaherpesvirus that primarily infects cells of the immune and vascular systems. HHV-8 interacts with and targets professional antigen presenting cells and influences their function. Infection alters the maturation, antigen presentation, and immune activation capabilities of certain dendritic cells (DC) despite non-robust lytic replication in these cells. DC sustains a low level of antiviral functionality during HHV-8 infection in vitro. This may explain the ability of healthy individuals to effectively control this virus without disease. Following an immune compromising event, such as organ transplantation or human immunodeficiency virus type 1 infection, a reduced cellular antiviral response against HHV-8 compounded with skewed DC cytokine production and antigen presentation likely contributes to the development of HHV-8 associated diseases, i.e., Kaposi's sarcoma and certain B cell lymphomas. In this review we focus on the role of DC in the establishment of HHV-8 primary and latent infection, the functional state of DC during HHV-8 infection, and the current understanding of the factors influencing virus-DC interactions in the context of HHV-8-associated disease

Translational nucleosome positioning: A computational study

Biological and Soft Matter Physic

Primary Effusion Lymphoma: An Untrivial Differential Diagnosis for Ascites

A primary effusion lymphoma is a rare type of non-Hodgkin's lymphoma where serous cavities are involved. That-cause peritoneal, pleural and pericardial effusions without any lymphadenopathy. They affect immunosuppressive patients with human herpes virus-8 being the suspected etiological agent. The prognosis is usually poor despite treatment. Herein, the case of an immunocompetent patient with ascites and pleural effusion diagnosed as primary effusion lymphoma is presented and discuss the case in the light of the current literature

Antibody Cross-Reactivity between Porcine Cytomegalovirus (PCMV) and Human Herpesvirus-6 (HHV-6)

Porcine cytomegalovirus (PCMV) infection is widely prevalent among pigs, and PCMV is one of the viruses which may be transmitted during xenotransplantation using pig cells, tissues, or organs. While human cytomegalovirus (HCMV) is a major risk factor for allotransplantation, it is still unclear whether PCMV is able to infect human cells or pose a risk for xenotransplantation. Previously, it was shown that transmission of PCMV after pig kidney to non-human primate transplantations resulted in a significantly reduced survival time of the transplanted organ. To detect PCMV, PCR-based and immunological methods were used. Screening of pigs by Western blot analyses using recombinant viral proteins revealed up to 100% of the tested animals to be infected. When the same method was applied to screen human sera for PCMV-reactive antibodies, positive Western blot results were obtained in butchers and workers in the meat industry as well as in normal blood donors. To exclude an infection of humans with PCMV, the sera were further investigated. PCMV is closely related to human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7), and a sequence alignment of glycoprotein B suggests that the antibodies may cross-react with identical epitope sequences. HCMV is not related with PCMV, and no correlation between antibody reactivity against PCMV and HCMV was detected. These data indicate that antibodies against PCMV found in humans are cross-reactive antibodies against HHV-6

An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity

The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects. These issues might be addressed by the additional use of host-directed antivirals (HDAs). As a strong input from long-term experiences with cancer therapies, host protein kinases may serve as HDA targets of mechanistically new antiviral drugs. The study demonstrates such a novel antiviral strategy by targeting the major virus-supportive host kinase CDK7. Importantly, this strategy focuses on highly selective, 3D structure-derived CDK7 inhibitors carrying a warhead moiety that mediates covalent target binding. In summary, the main experimental findings of this study are as follows: (1) the in vitro verification of CDK7 inhibition and selectivity that confirms the warhead covalent-binding principle (by CDK-specific kinase assays), (2) the highly pronounced antiviral efficacies of the hit compounds (in cultured cell-based infection models) with half-maximal effective concentrations that reach down to picomolar levels, (3) a particularly strong potency of compounds against strains and reporter-expressing recombinants of HCMV (using infection assays in primary human fibroblasts), (4) additional activity against further herpesviruses such as animal CMVs and VZV, (5) unique mechanistic properties that include an immediate block of HCMV replication directed early (determined by Western blot detection of viral marker proteins), (6) a substantial drug synergism in combination with MBV (measured by a Loewe additivity fixed-dose assay), and (7) a strong sensitivity of clinically relevant HCMV mutants carrying MBV or ganciclovir resistance markers. Combined, the data highlight the huge developmental potential of this host-directed antiviral targeting concept utilizing covalently binding CDK7 inhibitors

Kaposi's sarcoma of the hand mimicking squamous cell carcinoma in a woman with no evidence of HIV infection: a case report

<p>Abstract</p> <p>Introduction</p> <p>Kaposi's sarcoma is a vascular neoplasm mainly affecting the skin of the lower extremities. Although it is the most common neoplasm affecting patients with AIDS, sporadic cases in HIV-negative people have been reported. It is a lesion mainly affecting men and its clinical presentation presents a challenge, as it can resemble other benign or malignant skin lesions.</p> <p>Case presentation</p> <p>We report a rare case of Kaposi's sarcoma presenting in a 68-year-old Mediterranean woman with no evidence of HIV infection. The patient had a 6-month history of a slowly progressing pigmented lesion on the dorsum of her left hand. The lesion clinically resembled a squamous cell carcinoma. The patient was treated with a wide excision of the lesion and primary reconstruction with a full thickness skin graft. Histopathological and immunohistochemical analysis of the excised lesion revealed the presence of Kaposi's sarcoma. Serologic investigation for HIV was negative but polymerase chain reaction for human herpes virus type 8 infection was positive. Thorough clinical and imaging investigation of the abdomen and chest were both negative for loci of disease.</p> <p>Conclusion</p> <p>Kaposi's sarcoma, although rare in its sporadic form, should be considered in the differential diagnosis of indeterminate skin lesions, especially those affecting the extremities.</p