International Max Planck Research School for Advanced Methods in Process and Systems Engineering

Neutrophil infiltration into inflamed and infected tissues is a fundamental process of the innate immune response. While neutrophil interactions with the blood vessel wall have been intensely studied over the last decades, neutrophil dynamics beyond the vasculature have for a long time remained poorly investigated. Recent intravital microscopy studies of neutrophil populations directly at the site of tissue damage or microbial invasion have changed our perspective on neutrophil responses within tissues. Swarm-like migration patterns of neutrophils, referred to as 'neutrophil swarming', have been detected in diverse tissues under conditions of sterile inflammation and infection with various pathogens, including bacteria, fungi, and parasites. Current work has begun to unravel the molecular pathways choreographing the sequential phases of highly coordinated chemotaxis followed by neutrophil accumulation and the formation of substantial neutrophil clusters. It is now clear that intercellular communication among neutrophils amplifies their recruitment in a feed-forward manner, which provides them with a level of self-organization during neutrophil swarming. This review will summarize recent developments and current concepts on neutrophil swarming, an important process of the neutrophil tissue response with a critical role in maintaining the balance between host protection and inflammation-driven tissue destruction.

The Haber–Bosch process is viable for power-to-ammonia, as it can be operated for a wide range of the operating envelope while maintaining the process variables' operational, hydrogen feed intake and ammonia production flexibilities.

With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 10(7) cells/mL or even 10(8) cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to batch cultivations, keeping high yields for extended production times is still a challenge. Overall, we demonstrate that process intensification of cell culture-based viral vaccine production can be realized by the consequent application of fed-batch, perfusion, and continuous systems with a significant increase in productivity. The potential for even further improvements is high, considering recent developments in establishment of new (designer) cell lines, better characterization of host cell metabolism, advances in media design, and the use of mathematical models as a tool for process optimization and control.

Abstract The observed strengthening of the Northern Hemisphere (NH) polar vortex after tropical volcanic eruptions appears to be underestimated by coupled climate models. However, there are only a limited number of observed eruptions, which makes the attribution of volcanic signals difficult, because the polar vortex is also influenced by other external forcing factors as well as internal variability. We show with a 100‐member ensemble of historical (1850–2005) simulations with the Max Planck Institute Earth System Model that an ensemble larger than what is provided by the Coupled Model Intercomparison Project Phase 5 (CMIP5) models is needed to detect a statistically significant NH polar vortex strengthening. The most robust signal can be found when only the two strongest eruptions (Krakatau and Pinatubo) are considered in contrast to including smaller eruptions to increase the sample size. For these two strongest eruptions, the mean of 15 CMIP5 models shows a statistically significant strengthening of the NH polar vortex as well.

cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.

Abstract In the Southwest Pacific Ocean, waters transit from the subtropical gyre before being redistributed equatorward and poleward. While the mean pathways are known, the contribution to the mixing and transport of the water from mesoscale eddies has not been comprehensively investigated. In this research, satellite altimetry data, combined with an eddy detection and tracking algorithm is used to investigate the distribution and surface characteristics of mesoscale eddies in this region of complex bathymetry (10°S–30°S, 140°E–190°E). Detected eddies are then colocalized with in situ data from Argo floats to determine their vertical structure and the effect of eddies on the water masses. The numerous islands affect the eddy behavior as most eddies are formed in the lee of islands, propagate westward and decay when encountering shallow bathymetry. Eddies are sparse and short‐lived in the tropical area north of Fiji, impacting only the top 200 meters of water. They do not appear to be able to trap and transport waters in this region. In the Coral Sea, a region of lateral shear between currents transporting waters of different origins, eddies are more numerous and energetic. They affect the water properties down to at least 500 m depth, and anticyclonic eddies trap water to ∼200 m, contributing to the upper thermocline waters mixing and transport. South of New Caledonia, mesoscale eddies are ubiquitous, with typical lifetimes longer than 5 months. They affect the temperature, salinity, and velocities down to ∼1,000 m depth, and weakly contribute to the mixing of lower thermocline waters.

INTRODUCTION: Although mammographic density is an established risk factor for breast cancer, its use is limited in clinical practice because of a lack of automated and standardized measurement methods. The aims of this study were to evaluate a variety of automated texture features in mammograms as risk factors for breast cancer and to compare them with the percentage mammographic density (PMD) by using a case-control study design. METHODS: A case-control study including 864 cases and 418 controls was analyzed automatically. Four hundred seventy features were explored as possible risk factors for breast cancer. These included statistical features, moment-based features, spectral-energy features, and form-based features. An elaborate variable selection process using logistic regression analyses was performed to identify those features that were associated with case-control status. In addition, PMD was assessed and included in the regression model. RESULTS: Of the 470 image-analysis features explored, 46 remained in the final logistic regression model. An area under the curve of 0.79, with an odds ratio per standard deviation change of 2.88 (95% CI, 2.28 to 3.65), was obtained with validation data. Adding the PMD did not improve the final model. CONCLUSIONS: Using texture features to predict the risk of breast cancer appears feasible. PMD did not show any additional value in this study. With regard to the features assessed, most of the analysis tools appeared to reflect mammographic density, although some features did not correlate with PMD. It remains to be investigated in larger case-control studies whether these features can contribute to increased prediction accuracy.

FtsZ is a key component in bacterial cell division, being the primary protein of the presumably contractile Z ring. In vivo and in vitro, it shows two distinctive features that could so far, however, not be mechanistically linked: self-organization into directionally treadmilling vortices on solid supported membranes, and shape deformation of flexible liposomes. In cells, circumferential treadmilling of FtsZ was shown to recruit septum-building enzymes, but an active force production remains elusive. To gain mechanistic understanding of FtsZ dependent membrane deformations and constriction, we design an in vitro assay based on soft lipid tubes pulled from FtsZ decorated giant lipid vesicles (GUVs) by optical tweezers. FtsZ filaments actively transform these tubes into spring-like structures, where GTPase activity promotes spring compression. Operating the optical tweezers in lateral vibration mode and assigning spring constants to FtsZ coated tubes, the directional forces that FtsZ-YFP-mts rings exert upon GTP hydrolysis can be estimated to be in the pN range. They are sufficient to induce membrane budding with constricting necks on both, giant vesicles and E.coli cells devoid of their cell walls. We hypothesize that these forces result from torsional stress in a GTPase activity dependent manner.

Having children affects many aspects of people's lives. However, it remains unclear to what degree the challenges that come along with having children are associated with parents’ personality development. We addressed this question in two studies by investigating the relationship between parenting challenges and personality development in mothers of newborns (Study 1, N = 556) and the reciprocal associations between (mastering) parenting challenges and personality development in parents of adolescents (Study 2, N = 548 mothers and 460 fathers). In Study 1, we found the stress of having a newborn baby to be associated with declines in maternal Agreeableness, Conscientiousness, and Emotional Stability. Parenting challenges were also related to personality development in parents of adolescent children in Study 2, with parent–child conflict being reciprocally associated with decreases in Conscientiousness and Emotional Stability. Mastering parenting challenges in the form of high parenting self–efficacy, on the other hand, was found to be associated with increases in Agreeableness, Conscientiousness, and Emotional Stability, and vice versa. In sum, our results suggest that mastering the challenges associated with the social role of parenthood is one of the mechanisms underlying personality development in young and middle adulthood. Copyright © 2013 John Wiley & Sons, Ltd.

Abstract The current generation of Earth system models that participate in the Coupled Model Intercomparison Project phase 5 (CMIP5) does not, on average, produce a strengthened Northern Hemisphere (NH) polar vortex after large tropical volcanic eruptions as suggested by observational records. Here we investigate the impact of volcanic eruptions on the NH winter stratosphere with an ensemble of 20 model simulations of the Max Planck Institute Earth system model. We compare the dynamical impact in simulations of the very large 1815 Tambora eruption with the averaged dynamical response to the two largest eruptions of the CMIP5 historical simulations (the 1883 Krakatau and the 1991 Pinatubo eruptions). We find that for both the Tambora and the averaged Krakatau‐Pinatubo eruptions the radiative perturbation only weakly affects the polar vortex directly. The position of the maximum temperature anomaly gradient is located at approximately 30°N, where we obtain significant westerly zonal wind anomalies between 10 hPa and 30 hPa. Under the very strong forcing of the Tambora eruption, the NH polar vortex is significantly strengthened because the subtropical westerly wind anomalies are sufficiently strong to robustly alter the propagation of planetary waves. The average response to the eruptions of Krakatau and Pinatubo reveals a slight strengthening of the polar vortex, but individual ensemble members differ substantially, indicating that internal variability plays a dominant role. For the Tambora eruption the ensemble variability of the zonal mean temperature and zonal wind anomalies during midwinter and late winter is significantly reduced compared to the volcanically unperturbed period.

Parameter sensitivity analysis of mechanistic battery models has the power to quantify the individual and joint effects of parameters on the performance of lithium-ion cells. This information can be beneficial for industrial cell designs, cell testing, and battery management system (BMS) configurations. The numerical quantification of these parameter sensitivities, however, is challenging in terms of computational costs and is an active field of research. In this paper, based on a 3D multiphysics model, we conduct a global sensitivity analysis for the utilizable cell discharge capacity and the maximum cell temperature at the discharge rate of 1C. The least angle regression version of the polynomial chaos expansion (PCE) concept has been identified as an optimal trade-off between approximation power and computational complexity. As a result, the sensitivities of all parameters in the 3D multiphysics model were studied using a hierarchical design and a stepwise design. We conclude that the cell discharge capacity and the thermal behavior at 1C discharge are most sensitive to the electrode parameters and their pore structure. The results reveal different dependencies and lead to new insights for cell design and operation.

Abstract Since the onset of the pandemic, many SARS-CoV-2 variants have emerged, exhibiting substantial evolution in the virus’ spike protein 1 , the main target of neutralizing antibodies 2 . A plausible hypothesis proposes that the virus evolves to evade antibody-mediated neutralization (vaccine- or infection-induced) to maximize its ability to infect an immunologically experienced population 1,3 . Because viral infection induces neutralizing antibodies, viral evolution may thus navigate on a dynamic immune landscape that is shaped by local infection history. Here we developed a comprehensive mechanistic model, incorporating deep mutational scanning data 4,5 , antibody pharmacokinetics and regional genomic surveillance data, to predict the variant-specific relative number of susceptible individuals over time. We show that this quantity precisely matched historical variant dynamics, predicted future variant dynamics and explained global differences in variant dynamics. Our work strongly suggests that the ongoing pandemic continues to shape variant-specific population immunity, which determines a variant’s ability to transmit, thus defining variant fitness. The model can be applied to any region by utilizing local genomic surveillance data, allows contextualizing risk assessment of variants and provides information for vaccine design.

Abstract The stability of International Environmental Agreements (IEA) is analyzed by using game theory. The integrated assessment model FUND provides the cost‐benefit payoff functions of pollution abatement for sixteen different world regions. The farsighted stability concept of Chwe (1994) is used and solved by combinatorial algorithms. Farsighted stability assumes perfect foresight of the players and predicts which coalitions can be formed when players are farsighted. All farsightedly stable coalitions are found, and their improvement to environment and welfare is considerable. The farsightedly stable coalitions are refined further to preferred farsightedly stable coalitions, which are coalitions where the majority of coalition members reach higher profits in comparison with any other farsightedly stable coalitions. Farsightedly stable coalitions contribute more to the improvement of environment and welfare in comparison to D'Aspremont et al.'s (1983) stable ones. Considering multiple farsighted stable coalitions, participation in coalitions for environmental protection is significantly increased, which is an optimistic result of our game theoretical model.

OBJECTIVE: Retinal prostheses have shown promising results in restoring some visual perception to blind patients but successful identification of objects of different size remains a challenge. Here we investigated electrode-size specific stimulation thresholds and their variability for subretinal electrical stimulation. Our findings indicate the range of charge densities required to achieve identification of small objects and the object-size-specific scaling of stimulation threshold. APPROACH: Using biphasic voltage-limited current stimuli provided by a light-sensitive microchip, we determined threshold charge densities for stimulation with variable electrode sizes. The stimulated activation of the retinal network was identified by recording the spiking of retinal ganglion cells in photoreceptor-degenerated mouse rd10 retinas. Stimulation thresholds were determined for cells with saturating stimulus response relationships (SRRs) but not for cells characterized by monotonically increasing or decreasing SRRs. MAIN RESULTS: for an electrode diameter larger than 300 µm. This trend of decreasing threshold down to a plateau value was confirmed in wild-type mouse retina suggesting an underlying physiological source. SIGNIFICANCE: Our results suggest the following guidelines for retinal prosthetics employing biphasic current pulses. The encoding of small objects may be achieved through the activation of a confined set of different retinal ganglion cells, with individual stimulation thresholds spanning a wide range of charge densities. The encoding of increasing object sizes may be achieved by decreasing stimulation charge density.

Piccolo and Bassoon are the two largest cytomatrix of the active zone (CAZ) proteins involved in scaffolding and regulating neurotransmitter release at presynaptic active zones (AZs), but have long been discussed as being functionally redundant. We employed genetic manipulation to bring forth and segregate the role of Piccolo from that of Bassoon at central auditory synapses of the cochlear nucleus-the endbulbs of Held. These synapses specialize in high frequency synaptic transmission, ideally poised to reveal even subtle deficits in the regulation of neurotransmitter release upon molecular perturbation. Combining semi-quantitative immunohistochemistry, electron microscopy, and in vitro and in vivo electrophysiology we first studied signal transmission in Piccolo-deficient mice. Our analysis was not confounded by a cochlear deficit, as a short isoform of Piccolo ("Piccolino") present at the upstream ribbon synapses of cochlear inner hair cells (IHC), is unaffected by the mutation. Disruption of Piccolo increased the abundance of Bassoon at the AZs of endbulbs, while that of RIM1 was reduced and other CAZ proteins remained unaltered. Presynaptic fiber stimulation revealed smaller amplitude of the evoked excitatory postsynaptic currents (eEPSC), while eEPSC kinetics as well as miniature EPSCs (mEPSCs) remained unchanged. Cumulative analysis of eEPSC trains indicated that the reduced eEPSC amplitude of Piccolo-deficient endbulb synapses is primarily due to a reduced readily releasable pool (RRP) of synaptic vesicles (SV), as was corroborated by a reduction of vesicles at the AZ found on an ultrastructural level. Release probability seemed largely unaltered. Recovery from short-term depression was slowed. We then performed a physiological analysis of endbulb synapses from mice which, in addition to Piccolo deficiency, lacked one functional allele of the Bassoon gene. Analysis of the double-mutant endbulbs revealed an increase in release probability, while the synapses still exhibited the reduced RRP, and the impairment in SV replenishment was exacerbated. We propose additive roles of Piccolo and Bassoon in SV replenishment which in turn influences the organization and size of the RRP, and an additional role of Bassoon in regulation of release probability.

In the field of chemical engineering, mathematical models have been proven to be an indispensable tool for process analysis, process design, and condition monitoring. To gain the most benefit from model-based approaches, the implemented mathematical models have to be based on sound principles, and they need to be calibrated to the process under study with suitable model parameter estimates. Often, the model parameters identified by experimental data, however, pose severe uncertainties leading to incorrect or biased inferences. This applies in particular in the field of pharmaceutical manufacturing, where usually the measurement data are limited in quantity and quality when analyzing novel active pharmaceutical ingredients. Optimally designed experiments, in turn, aim to increase the quality of the gathered data in the most efficient way. Any improvement in data quality results in more precise parameter estimates and more reliable model candidates. The applied methods for parameter sensitivity analyses and design criteria are crucial for the effectiveness of the optimal experimental design. In this work, different design measures based on global parameter sensitivities are critically compared with state-of-the-art concepts that follow simplifying linearization principles. The efficient implementation of the proposed sensitivity measures is explicitly addressed to be applicable to complex chemical engineering problems of practical relevance. As a case study, the homogeneous synthesis of 3,4-dihydro-1H-1-benzazepine-2,5-dione, a scaffold for the preparation of various protein kinase inhibitors, is analyzed followed by a more complex model of biochemical reactions. In both studies, the model-based optimal experimental design benefits from global parameter sensitivities combined with proper design measures.

Although most mammals heal injured tissues and organs with scarring, spiny mice ( Acomys ) naturally regenerate skin and complex musculoskeletal tissues. Now, the core signaling pathways driving mammalian tissue regeneration are poorly characterized. Here, we show that, while immediate extracellular signal-regulated kinase (ERK) activation is a shared feature of scarring ( Mus ) and regenerating ( Acomys ) injuries, ERK activity is only sustained at high levels during complex tissue regeneration. Following ERK inhibition, ear punch regeneration in Acomys shifted toward fibrotic repair. Using single-cell RNA sequencing, we identified ERK-responsive cell types. Loss- and gain-of-function experiments prompted us to uncover fibroblast growth factor and ErbB signaling as upstream ERK regulators of regeneration. The ectopic activation of ERK in scar-prone injuries induced a pro-regenerative response, including cell proliferation, extracellular matrix remodeling, and hair follicle neogenesis. Our data detail an important distinction in ERK activity between regenerating and poorly regenerating adult mammals and open avenues to redirect fibrotic repair toward regenerative healing.

BACKGROUND: Pericytes and vascular smooth muscle cells, collectively known as mural cells, are recruited through PDGFB (platelet-derived growth factor B)-PDGFRB (platelet-derived growth factor receptor beta) signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions. Here, we characterize the role of the transcription factor SRF (serum response factor) in MCs and study its function in developmental and pathological contexts. METHODS: gene deletion and studied its consequences during retinal angiogenesis using RNA-sequencing, immunohistology, in vivo live imaging, and in vitro techniques. RESULTS: By postnatal day 6, pericytes lacking SRF were morphologically abnormal and failed to properly comigrate with angiogenic sprouts. As a consequence, pericyte-deficient vessels at the retinal sprouting front became dilated and leaky. By postnatal day 12, also the vascular smooth muscle cells had lost SRF, which coincided with the formation of pathological arteriovenous shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF (myocardin-related transcription factor) cofactors. We further show that MRTF-SRF signaling promotes pathological pericyte activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging, and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone. CONCLUSIONS: SRF is crucial for distinct functions in pericytes and vascular smooth muscle cells. SRF directs pericyte migration downstream of PDGFRB signaling and mediates pathological pericyte activation during ischemic retinopathy. In vascular smooth muscle cells, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of arteriovenous shunts. These essential roles in physiological and pathological contexts provide a rationale for novel therapeutic approaches through targeting SRF activity in MCs.

With growing interest in the simulation of compressible flows using the lattice Boltzmann (LB) method, a number of different approaches have been developed. These methods can be classified as pertaining to one of two major categories: (i) solvers relying on high-order stencils recovering the Navier-Stokes-Fourier equations, and (ii) approaches relying on classical first-neighbour stencils for the compressible Navier-Stokes equations coupled to an additional (LB-based or classical) solver for the energy balance equation. In most cases, the latter relies on a thermal Hermite expansion of the continuous equilibrium distribution function (EDF) to allow for compressibility. Even though recovering the correct equation of state at the Euler level, it has been observed that deviations of local flow temperature from the reference can result in instabilities and/or over-dissipation. The aim of the present study is to evaluate the stability domain of different EDFs, different collision models, with and without the correction terms for the third-order moments. The study is first based on a linear von Neumann analysis. The correction term for the space- and time-discretized equations is derived via a Chapman-Enskog analysis and further corroborated through spectral dispersion-dissipation curves. Finally, a number of numerical simulations are performed to illustrate the proposed theoretical study. This article is part of the theme issue 'Fluid dynamics, soft matter and complex systems: recent results and new methods'.

The lattice kinetic scheme (LKS), a modified version of the classical single relaxation time (SRT) lattice Boltzmann method, was initially developed as a suitable numerical approach for non-Newtonian flow simulations and a way to reduce memory consumption of the original SRT approach. The better performances observed for non-Newtonian flows are mainly due to the additional degree of freedom allowing an independent control over the relaxation of higher-order moments, independently from the fluid viscosity. Although widely applied to fluid flow simulations, no theoretical analysis of LKS has been performed. The present work focuses on a systematic von Neumann analysis of the linearized collision operator. Thanks to this analysis, the effects of the modified collision operator on the stability domain and spectral behavior of the scheme are clarified. Results obtained in this study show that correct choices of the "second relaxation coefficient" lead, to a certain extent, to a more consistent dispersion and dissipation for large values of the first relaxation coefficient. Furthermore, appropriate values of this parameter can lead to a larger linear stability domain. At moderate and low values of viscosity, larger values of the free parameter are observed to increase dissipation of kinetic modes, while leaving the acoustic modes untouched and having a less pronounced effect on the convective mode. This increased dissipation leads in general to less pronounced sources of nonlinear instability, thus improving the stability of the LKS.