Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model

Fibrotic myocardial remodeling is typically accompanied by the appearance of myofibroblasts (MFBs). In vitro, MFBs were shown to slow conduction and precipitate ectopic activity following gap junctional coupling to cardiomyocytes (CMCs). To gain further mechanistic insights into this arrhythmogenic MFB-CMC crosstalk, we performed numerical simulations in cell-based high-resolution two-dimensional tissue models that replicated experimental conditions. Cell dimensions were determined using confocal microscopy of single and co-cultured neonatal rat ventricular CMCs and MFBs. Conduction was investigated as a function of MFB density in three distinct cellular tissue architectures: CMC strands with endogenous MFBs, CMC strands with coating MFBs of two different sizes, and CMC strands with MFB inserts. Simulations were performed to identify individual contributions of heterocellular gap junctional coupling and of the specific electrical phenotype of MFBs. With increasing MFB density, both endogenous and coating MFBs slowed conduction. At MFB densities of 5-30%, conduction slowing was most pronounced in strands with endogenous MFBs due to the MFB-dependent increase in axial resistance. At MFB densities >40%, very slow conduction and spontaneous activity was primarily due to MFB-induced CMC depolarization. Coating MFBs caused non-uniformities of resting membrane potential, which were more prominent with large than with small MFBs. In simulations of MFB inserts connecting two CMC strands conduction delays increased with increasing insert lengths and block appeared for inserts >1.2 mm. Thus, electrophysiological properties of engineered CMC-MFB co-cultures depend on MFB density, MFB size and their specific positioning in respect to CMCs. These factors may influence conduction characteristics in the heterocellular myocardium

Challenges in Coagulation Management in Neurosurgical Diseases: A Scoping Review, Development, and Implementation of Coagulation Management Strategies

Bleeding and thromboembolic (TE) complications in neurosurgical diseases have a detrimental impact on clinical outcomes. The aim of this study is to provide a scoping review of the available literature and address challenges and knowledge gaps in the management of coagulation disorders in neurosurgical diseases. Additionally, we introduce a novel research project that seeks to reduce coagulation disorder-associated complications in neurosurgical patients. The risk of bleeding after elective craniotomy is about 3%, and higher (14-33%) in other indications, such as trauma and intracranial hemorrhage. In spinal surgery, the incidence of postoperative clinically relevant bleeding is approximately 0.5-1.4%. The risk for TE complications in intracranial pathologies ranges from 3 to 20%, whereas in spinal surgery it is around 7%. These findings highlight a relevant problem in neurosurgical diseases and current guidelines do not adequately address individual circumstances. The multidisciplinary COagulation MAnagement in Neurosurgical Diseases (COMAND) project has been developed to tackle this challenge by devising an individualized coagulation management strategy for patients with neurosurgical diseases. Importantly, this project is designed to ensure that these management strategies can be readily implemented into healthcare practices of different types and with sustainable integration

Differential trafficking of ligands trogocytosed via CD28 versus CTLA4 promotes collective cellular control of co-stimulation

Intercellular communication is crucial for collective regulation of cellular behaviors. While clustering T cells have been shown to mutually control the production of key communication signals, it is unclear whether they also jointly regulate their availability and degradation. Here we use newly developed reporter systems, bioinformatic analyses, protein structure modeling and genetic perturbations to assess this. We find that T cells utilize trogocytosis by competing antagonistic receptors to differentially control the abundance of immunoregulatory ligands. Specifically, ligands trogocytosed via CD28 are shuttled to the T cell surface, enabling them to co-stimulate neighboring T cells. In contrast, CTLA4-mediated trogocytosis targets ligands for degradation. Mechanistically, this fate separation is controlled by different acid-sensitivities of receptor-ligand interactions and by the receptor intracellular domains. The ability of CD28 and CTLA4 to confer different fates to trogocytosed ligands reveals an additional layer of collective regulation of cellular behaviors and promotes the robustness of population dynamics.Fil: Zenke, Simon. Albert Ludwigs University of Freiburg; AlemaniaFil: Sica, Mauricio Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Steinberg, Florian. Albert Ludwigs University of Freiburg; AlemaniaFil: Braun, Julia. Albert Ludwigs University of Freiburg; AlemaniaFil: Zink, Alicia. Albert Ludwigs University of Freiburg; AlemaniaFil: Gavrilov, Alina. Max Planck Institute of Immunobiology and Epigenetics; AlemaniaFil: Hilger, Alexander. Albert Ludwigs University of Freiburg; AlemaniaFil: Arra, Aditya. Otto-von-Guericke-Universität Magdeburg; AlemaniaFil: Brunner Weinzierl, Monika. Otto-von-Guericke-Universität Magdeburg; AlemaniaFil: Elling, Roland. Albert Ludwigs University of Freiburg; AlemaniaFil: Beyersdorf, Niklas. Universität Würzburg; AlemaniaFil: Lämmermann, Tim. Albert Ludwigs University of Freiburg; AlemaniaFil: Smulski, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rohr, Jan C.. Albert Ludwigs University of Freiburg; Alemani

Explaining the variation in impacts of non-native plants on local-scale species richness: the role of phylogenetic relatedness

ABSTRACT Aim To assess how the magnitude of impacts of non-native plants on species richness of resident plants and animals varies in relation to the traits and phylogenetic position of the non-native as well as characteristics of the invaded site. Location Global. Methods Meta-analysis and phylogenetic regressions based on 216 studies were used to examine the effects of 96 non-native plant species on species richness of resident plants and animals while considering differences in non-native species traits (life-form, clonality or vegetative reproduction, and nitrogen-fixing ability) and characteristics of the invaded site (ecosystem type, insularity and climatic region). Results Plots with non-native plants had lower resident plant (-20.5%) and animal species richness (-26.4%) than paired uninvaded control plots. Nitrogenfixing ability, followed by phylogeny and clonality were the best predictors of the magnitude of impacts of non-native plants on native plant species richness. Nonnitrogen-fixing and clonal non-native plants reduced species richness more than nitrogen-fixing and non-clonal invaders. However, life-form and characteristics of the invaded sites did not appear to be important. In the case of resident animal species richness, only the phylogenetic position of the non-native and whether invaded sites were islands or not influenced impacts, with a more pronounced decrease found on islands than mainlands. Main conclusions The presence of a phylogenetic signal on the magnitude of the impacts of non-native plants on resident plant and animal richness indicates that closely related non-native plants tend to have similar impacts. This suggests that the magnitude of the impact might depend on shared plant traits not explored in our study. Our results therefore support the need to include the phylogenetic similarity of non-native plants to known invaders in risk assessment analysis

Explaining the variation in impacts of non-native plants on local-scale species richness: the role of phylogenetic relatedness

ABSTRACT Aim To assess how the magnitude of impacts of non-native plants on species richness of resident plants and animals varies in relation to the traits and phylogenetic position of the non-native as well as characteristics of the invaded site. Location Global. Methods Meta-analysis and phylogenetic regressions based on 216 studies were used to examine the effects of 96 non-native plant species on species richness of resident plants and animals while considering differences in non-native species traits (life-form, clonality or vegetative reproduction, and nitrogen-fixing ability) and characteristics of the invaded site (ecosystem type, insularity and climatic region). Results Plots with non-native plants had lower resident plant (-20.5%) and animal species richness (-26.4%) than paired uninvaded control plots. Nitrogenfixing ability, followed by phylogeny and clonality were the best predictors of the magnitude of impacts of non-native plants on native plant species richness. Nonnitrogen-fixing and clonal non-native plants reduced species richness more than nitrogen-fixing and non-clonal invaders. However, life-form and characteristics of the invaded sites did not appear to be important. In the case of resident animal species richness, only the phylogenetic position of the non-native and whether invaded sites were islands or not influenced impacts, with a more pronounced decrease found on islands than mainlands. Main conclusions The presence of a phylogenetic signal on the magnitude of the impacts of non-native plants on resident plant and animal richness indicates that closely related non-native plants tend to have similar impacts. This suggests that the magnitude of the impact might depend on shared plant traits not explored in our study. Our results therefore support the need to include the phylogenetic similarity of non-native plants to known invaders in risk assessment analysis

PITX1 is a regulator of TERT expression in prostate cancer with prognostic power

Simple Summary Most prostate cancer is of an indolent form and is curable. However, some prostate cancer belongs to rather aggressive subtypes leading to metastasis and death, and immediate therapy is mandatory. However, for these, the therapeutic options are highly invasive, such as radical prostatectomy, radiation or brachytherapy. Hence, a precise diagnosis of these tumor subtypes is needed, and the thus far applied diagnostic means are insufficient for this. Besides this, for their endless cell divisions, prostate cancer cells need the enzyme telomerase to elongate their telomeres (chromatin endings). In this study, we developed a gene regulatory model based on large data from transcription profiles from prostate cancer and chromatin-immuno-precipitation studies. We identified the developmental regulator PITX1 regulating telomerase. Besides observing experimental evidence of PITX1′s functional role in telomerase regulation, we also found PITX1 serving as a prognostic marker, as concluded from an analysis of more than 15,000 prostate cancer samples. Abstract The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of TERT , transcription factors regulating TERT may suit as prognostic markers. To identify transcription factors regulating TERT , we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as TERT regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates TERT expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length

Convolutional Neural Networks Applied to Neutrino Events in a Liquid Argon Time Projection Chamber

We present several studies of convolutional neural networks applied to data coming from the MicroBooNE detector, a liquid argon time projection chamber (LArTPC). The algorithms studied include the classification of single particle images, the localization of single particle and neutrino interactions in an image, and the detection of a simulated neutrino event overlaid with cosmic ray backgrounds taken from real detector data. These studies demonstrate the potential of convolutional neural networks for particle identification or event detection on simulated neutrino interactions. We also address technical issues that arise when applying this technique to data from a large LArTPC at or near ground level

Noise Characterization and Filtering in the MicroBooNE Liquid Argon TPC

The low-noise operation of readout electronics in a liquid argon time projection chamber (LArTPC) is critical to properly extract the distribution of ionization charge deposited on the wire planes of the TPC, especially for the induction planes. This paper describes the characteristics and mitigation of the observed noise in the MicroBooNE detector. The MicroBooNE's single-phase LArTPC comprises two induction planes and one collection sense wire plane with a total of 8256 wires. Current induced on each TPC wire is amplified and shaped by custom low-power, low-noise ASICs immersed in the liquid argon. The digitization of the signal waveform occurs outside the cryostat. Using data from the first year of MicroBooNE operations, several excess noise sources in the TPC were identified and mitigated. The residual equivalent noise charge (ENC) after noise filtering varies with wire length and is found to be below 400 electrons for the longest wires (4.7 m). The response is consistent with the cold electronics design expectations and is found to be stable with time and uniform over the functioning channels. This noise level is significantly lower than previous experiments utilizing warm front-end electronics.Comment: 36 pages, 20 figure