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Abstract Human-based modelling and simulation offer an ideal testbed for novel medical therapies to guide experimental and clinical studies. Myocardial infarction (MI) is a common cause of heart failure and mortality, for which novel therapies are urgently needed. Although cell therapy offers promise, electrophysiological heterogeneity raises pro-arrhythmic safety concerns, where underlying complex spatio-temporal dynamics cannot be investigated experimentally. Here, after demonstrating credibility of the modelling and simulation framework, we investigate cell therapy in acute versus chronic MI and the role of cell heterogeneity, scar size and the Purkinje system. Simulations agreed with experimental and clinical recordings from ionic to ECG dynamics in acute and chronic infarction. Following cell delivery, spontaneous beats were facilitated by heterogeneity in cell populations, chronic MI due to tissue depolarisation and slow sinus rhythm. Subsequent re-entrant arrhythmias occurred, in some instances with Purkinje involvement and their susceptibility was enhanced by impaired Purkinje-myocardium coupling, large scars and acute infarction. We conclude that homogeneity in injected ventricular-like cell populations minimises their spontaneous beating, which is enhanced by chronic MI, whereas a healthy Purkinje-myocardium coupling is key to prevent subsequent re-entrant arrhythmias, particularly for large scars.

Quantitative Systems Pharmacology (QSP) has become a powerful tool in the drug development landscape. To facilitate its continued implementation and to further enhance its applicability, a symbiotic approach in which QSP is combined with artificial intelligence (AI) and machine learning (ML) seems key. This manuscript presents four case examples where the application of a symbiotic approach could unlock new insights from multidimensional data, including real-world data, potentially leading to breakthroughs in drug development. Besides the remarkable benefits (gAIns) that the symbiosis can offer, it does also carry potential challenges (pAIns) such as how to assess and quantify uncertainty, bias and error. Hence, to ensure a successful implementation, arising pAIns need to be acknowledged and carefully addressed. Successful implementation of the symbiotic QSP and ML/AI approach has the potential to serve as a catalyst, paving the way for a paradigm shift in drug development.

Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A major route by which COVID-19 impacts different organs is via the vascular system. We studied the impact of apolipoprotein E (APOE) genotype and inflammation on vascular infectivity by pseudo-typed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses in mouse and human cultured endothelial cells and pericytes. Possessing the APOE4 allele or having existing systemic inflammation is known to enhance the severity of COVID-19. Using targeted replacement human APOE3 and APOE4 mice and inflammation induced by bacterial lipopolysaccharide (LPS), we investigated infection by SARS-CoV-2. Here, we show that infectivity was higher in murine cerebrovascular pericytes compared to endothelial cells and higher in cultures expressing APOE4. Furthermore, increasing the inflammatory state of the cells by prior incubation with LPS increased infectivity into human and mouse pericytes and human endothelial cells. Our findings provide insights into the mechanisms underlying severe COVID-19 infection, highlighting how risk factors such as APOE4 genotype and prior inflammation may exacerbate disease severity by augmenting the virus’s ability to infect vascular cells.

Abstract Genome-wide association studies identified several disease-causing mutations in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the contribution of genetic variants to pathway disturbances and their cell type-specific variations, especially in glia, is poorly understood. We integrated ALS GWAS-linked gene networks with human astrocyte-specific multi-omics datasets to elucidate pathognomonic signatures. It predicts that KIF5A, a motor protein kinesin-1 heavy-chain isoform, previously detected only in neurons, can also potentiate disease pathways in astrocytes. Using postmortem tissue and super-resolution structured illumination microscopy in cell-based perturbation platforms, we provide evidence that KIF5A is present in astrocyte processes and its deficiency disrupts structural integrity and mitochondrial transport. We show that this may underly cytoskeletal and trafficking changes in SOD1 ALS astrocytes characterised by low KIF5A levels, which can be rescued by c-Jun N-terminal Kinase-1 (JNK1), a kinesin transport regulator. Altogether, our pipeline reveals a mechanism controlling astrocyte process integrity, a pre-requisite for synapse maintenance and suggests a targetable loss-of-function in ALS.

Human dimensions in endangered species conservation are often overlooked. However, including human dimensions in conservation projects can help conservationists integrate social and ecological dimensions and investigate individual or society’s perspectives toward conservation efforts. The aim of this study was to investigate how visitors of a protected area perceived the conservation of the native white-clawed crayfish (Austropotamobius pallipes), a species recently brought to disappearance by the introduction of the spiny-cheek crayfish (Faxonius limosus). From August to October 2017, we distributed a questionnaire to park visitors, aiming to: (i) identify behaviors that could affect the conservation of the native crayfish after reintroduction; (ii) investigate if visitors’ awareness and knowledge of native freshwater crayfish may increase approval for conservation initiatives. Of the 290 respondents, most (73%) had never heard of alien species. The respondents’ inclination to be favorable to resource investment and alien crayfish eradication and to perform specific educational training was significantly related to their knowledge of crayfish features. Knowledge of freshwater crayfish features resulted in being a main determinant in affecting visitors’ attitudes towards conservation initiatives. These results confirm that visitors’ awareness can increase approval for conservation programs and the importance of investigating the proper human dimensions before establishing management actions for endangered species.

South Africa's wide range of animal facilities offers many different types of Animal-Visitor Interactions, wild animal encounters where animals and visitors come closer than in normal circumstances. The aim of this study was to provide a map of the ethically relevant aspects involved in AVIs in South Africa as a first step towards regulating these activities. A participative approach based on the ethical matrix, a tool which organizes the ethical standings of the stakeholders by three bearing ethical principles (wellbeing, autonomy, fairness), was applied. The matrix was populated through a top-down approach and refined by engaging stakeholders in a workshop and two online self-administrated surveys. The outcome is a map of the value demands concerning Animal Visitor Interactions. This map shows how the ethical acceptability of AVIs is linked to different relevant issues like animal welfare, education, biodiversity conservation, sustainability, human competency, facility mission, impact on scientific research and socio-economic outcomes. In addition, results highlighted the importance of cooperation among stakeholders and suggested that attention for animal welfare can inform decision making and inspire a multidisciplinary approach in implementing a regulatory frame for South African wildlife facilities.

Quantitative systems pharmacology (QSP) modeling has become an increasingly popular approach impacting our understanding of disease mechanisms and helping predict patients’ treatment responses to facilitate study design or development go/no-go decisions. In this paper, we highlight the notable contributions and opportunities that QSP approaches are to offer during the drug development process by sharing three examples that have facilitated internal decisions. The barriers to successful applications and the factors that facilitate the success of the modeling approach is discussed.

In our everyday experience, life, environment, and nature are connected and we tend to confuse the value we assign to them. One way around this issue is to analyze our intuitions on the terraformation of other planets such as Mars. In this way, we are forced to consider whether the original abiotic nature has a value of some kind regardless of its capacity to support ecosystems and life, what kind of value this might be, and what weight it might have when compared with other values. In this contribution, I will draw a map of the possible answers to these questions by analyzing the different perspectives brought forth by some of the main characters in K. S. Robinson's The Mars Trilogy. In this way, it will be possible to observe that, while on Earth instrumental and non-instrumental kinds of environmental value generally concur and support each other, in an abiotic landscape, such as that offered (we assume) by Mars, they may conflict.

INTRODUCTION: In tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels contribute to disease‐associated abnormalities in multiple neurodegenerative diseases. METHODS: To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age‐matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons. RESULTS: Expression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization‐induced membrane voltage "sag" and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents. DISCUSSION: Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network‐wide structural and functional synaptic deficits. Highlights: Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are functionally linked to the development of tauopathy.Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy.Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization‐induced membrane voltage "sag" demonstrating a detrimental effect of tau abnormalities on HCN channel function.Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice. [ABSTRACT FROM AUTHOR]

Originally applied on domestic and lab animals, assisted reproduction technologies (ARTs) have also found application in conservation breeding programs, where they can make the genetic management of populations more efficient, and increase the number of individuals per generation. However, their application in wildlife conservation opens up new ethical scenarios that have not yet been fully explored. This study presents a frame for the ethical analysis of the application of ART procedures in conservation based on the Ethical Matrix (EM), and discusses a specific case study—ovum pick-up (OPU) procedures performed in the current conservation efforts for the northern white rhinoceros (Ceratotherium simum cottoni)—providing a template for the assessment of ART procedures in projects involving other endangered species.

Nowadays, most zoos have taken prominent and active positions in endangered species conservation and educating visitors about the value of biodiversity. However, to be effective and trusted in their mission, they must act ethically and have a good reputation. Yet, the drivers that can influence their reputation are still little investigated, and there are still few studies focused on assessing the reputation of these institutions. In the present work, we report the development of a tool, the Zoo Ethical Reputation Survey (ZERS), and its pilot application to assess the opinions of the visitors of two zoos, one in Italy and one in Germany, on drivers that may influence the ethical reputation of zoos. Preliminary results based on the answers of 274 respondents show that visitors’ opinions on zoos acting with ethical responsibility are correlated with emotional appeal and familiarity with these institutions. The application of ZERS can help zoos identify weaknesses in their reputation and develop new strategies to improve people’s attitudes towards them, bringing many benefits to the individual zoo and zoological institutions in general.

An alternative definition to the main frequency of an ultrashort laser pulse, named principal frequency (ω_{P}), was recently introduced in E. G. Neyra et al. [Phys. Rev. A 103, 053124 (2021)2469-992610.1103/PhysRevA.103.053124], resulting in a more transparent description of the nonlinear dynamics of a system driven by this coherent source. In this paper, we extend the definition of ω_{P} incorporating the spectral phase of the pulse. This upgraded definition allow us to deal with superoscillatory pulses as well as to characterize subcycle pulses with a complex spectral content. Simultaneously, we study the nonlinear interaction between a few-cycle superoscillatory pulse with a gaseous system, analyzing the spectral characteristics of the fundamental, third, and fifth harmonics. Here, we make use of an ab initio quantum mechanical approach, supplemented with a wavelet analysis. We show that the spectral characteristics of the low-order harmonics are very well explained in terms of ω_{P}, as well as the effective bandwidth of the superoscillatory pulse. Our findings reinforce previous results that showed an increase of the effective bandwidth in the superoscillatory region and the possibility to generate unique frequencies by a linear synthesis. We thus open not only perspectives in ultrafast optics, exploring pathways toward the generation of fully tunable strong and short coherent sources, but also discuss possible extensions of the concepts presented here to other wave phenomena that can be found in acoustics, signal processing, and quantum mechanics.

Decision making-process in conservation can be very complex, having to deal with various value dimensions and potential conflicts. In fact, conflicts and competing interests between stakeholders are among the most quoted reasons for failure of projects. Ethical analysis can be helpful in this regard. In this paper we present a revision of the Ethical Matrix specifically tailored to decision-making processes in conservation. The Ethical Matrix is a conceptual tool devised to help decision-makers by supplying them with a framework of the ethically relevant aspects involved in decision-making process. It was originally developed for the ethical assessment of agri-food biotechnologies and later has been applied to other fields. The revised version we propose here has been designed for the ethical analysis of conservation priority-setting and impact. As conservation can raise many ethical relevant controversies, conceptual tools like the one presented here can be of help for conservationists, providing a map of the value demands involved. This map can be used to question the reasonableness of the value judgments, estimate the impact of different courses of actions, anticipate conflicts, and rank their severeness.

Based on the experience of developing and teaching an introductory course on Spanish-English interpretation, this study will situate and justify translation, more specifically interpreting, as an important component for language development. The goal is to analyze ways the development and implementation of an interpreting course (focusing on consecutive and simultaneous interpreting and sight translation) can help develop students' language, cultural, subject, and overall transfer competencies, categories enumerated by Albrecht Neubert (2000). Based on student feedback, learning outcomes, and a description of teaching methods that combine the process-oriented and product-oriented approaches, this study will also point out that second language acquisition (SLA) findings can inform the teaching and the practice of professional translation (Colina 2006: 213). In addition, it will illustrate that an interpreting course is in alignment with the National Standards for Learning Languages and helps not only improve language skills and interpreting techniques but also opens minds to a new culture, improves cross-cultural and intercultural communication, strengthens public speaking skills, boosts confidence, and helps expand personal horizons.

Abstract Tau is known for its pathological role in neurodegenerative diseases, including Alzheimer’s disease (AD) and other tauopathies. Tau is found in many subcellular compartments such as the cytosol and the nucleus. Although its normal role in microtubule binding is well established, its nuclear role is still unclear. Here, we reveal that tau localises to the nucleolus in undifferentiated and differentiated neuroblastoma cells (SHSY5Y), where it associates with TIP5, a key player in heterochromatin stability and ribosomal DNA (rDNA) transcriptional repression. Immunogold labelling on human brain sample confirms the physiological relevance of this finding by showing tau within the nucleolus colocalises with TIP5. Depletion of tau results in an increase in rDNA transcription with an associated decrease in heterochromatin and DNA methylation, suggesting that under normal conditions tau is involved in silencing of the rDNA. Cellular stress induced by glutamate causes nucleolar stress associated with the redistribution of nucleolar non-phosphorylated tau, in a similar manner to fibrillarin, and nuclear upsurge of phosphorylated tau (Thr231) which doesn’t colocalise with fibrillarin or nucleolar tau. This suggests that stress may impact on different nuclear tau species. In addition to involvement in rDNA transcription, nucleolar non-phosphorylated tau also undergoes stress-induced redistribution similar to many nucleolar proteins.

Assisted reproductive technologies (ARTs) can make a difference in biodiversity conservation. Their application, however, can create risks and raise ethical issues that need addressing. Unfortunately, there is a lack of attention to the topic in the scientific literature and, to our knowledge, there is no tool for the ethical assessment of ARTs in the context of conservation that has been described. This paper reports the first applications of the Ethical Assessment Tool (ETHAS) to trans-rectal ovum pick-up (OPU) and in vitro fertilization (IVF) procedures used in a northern white rhinoceros (Ceratotherium simum cottoni) conservation project. The ETHAS consists of two checklists, the Ethical Evaluation Sheet and the Ethical Risk Assessment, and is specifically customized for each ART procedure. It provides an integrated, multilevel and standardized self-assessment of the procedure under scrutiny, generating an ethical acceptability ranking (totally, partially, not acceptable) and a risk rank (low, medium, high), and, hence, allows for implementing measures to address or manage issues beforehand. The application of the ETHAS to the procedures performed on the northern white rhinoceros was effective in ensuring a high standard of procedures, contributing to the acceptability and improved communication among the project’s partners. In turn, the tool itself was also refined through an iterative consultation process between experts and stakeholders.

Mechanical circulatory support devices, such as total artificial hearts and left ventricular assist devices, rely on external energy sources for their continuous operation. Clinically approved power supplies rely on percutaneous cables connecting an external energy source to the implanted device with the associated risk of infections. One alternative, investigated in the 70s and 80s, employs a fully implanted nuclear power source. The heat generated by the nuclear decay can be converted into electricity to power circulatory support devices. Due to the low conversion efficiencies, substantial levels of waste heat are generated and must be dissipated to avoid tissue damage, heat stroke, and death. The present work computationally evaluates the ability of the blood flow in the descending aorta to remove the locally generated waste heat for subsequent full-body distribution and dissipation, with the specific aim of investigating methods for containment of local peak temperatures within physiologically acceptable limits. To this aim, coupled fluid–solid heat transfer computational models of the blood flow in the human aorta and different heat exchanger architectures are developed. Particle tracking is used to evaluate temperature histories of cells passing through the heat exchanger region. The use of the blood flow in the descending aorta as a heat sink proves to be a viable approach for the removal of waste heat loads. With the basic heat exchanger design, blood thermal boundary layer temperatures exceed 50°C, possibly damaging blood cells and proteins. Improved designs of the heat exchanger, with the addition of fins and heat guides, allow for drastically lower blood temperatures, possibly leading to a more biocompatible implant. The ability to maintain blood temperatures at biologically compatible levels will ultimately allow for the body-wise distribution, and subsequent dissipation, of heat loads with minimum effects on the human physiology.

The biomechanics-based Abdominal Aortic Aneurysm (AAA) rupture risk assessment has gained considerable scientific and clinical momentum. However, such studies have mainly focused on information at a single time point, and little is known about how AAA properties change over time. Consequently, the present study explored how geometry, wall stress-related and blood flow-related biomechanical properties change during AAA expansion. Four patients with a total of 23 Computed Tomography-Angiography (CT-A) scans at different time points were analyzed. At each time point, patient-specific properties were extracted from (i) the reconstructed geometry, (ii) the computed wall stress at Mean Arterial Pressure (MAP), and (iii) the computed blood flow velocity at standardized inflow and outflow conditions. Testing correlations between these parameters identified several nonintuitive dependencies. Most interestingly, the Peak Wall Rupture Index (PWRI) and the maximum Wall Shear Stress (WSS) independently predicted AAA volume growth. Similarly, Intra-luminal Thrombus (ILT) volume growth depended on both the maximum WSS and the ILT volume itself. In addition, ILT volume, ILT volume growth, and maximum ILT layer thickness correlated with PWRI as well as AAA volume growth. Consequently, a large ILT volume as well as fast increase of ILT volume over time may be a risk factor for AAA rupture. However, tailored clinical studies would be required to test this hypothesis and to clarify whether monitoring ILT development has any clinical benefit.

Tracking cells and proteins’ phenotypic changes in deep suspensions is critical for the direct imaging of blood-related phenomena in in vitro replica of cardiovascular systems and blood-handling devices. This paper introduces fluorescence imaging techniques for space and time resolved detection of platelet activation, von Willebrand factor (VWF) conformational changes, and VWF-platelet interaction in deep suspensions. Labeled VWF, platelets, and VWF-platelet strands are suspended in deep cuvettes, illuminated, and imaged with a high-sensitivity EM-CCD camera, allowing detection using an exposure time of 1 ms. In-house postprocessing algorithms identify and track the moving signals. Recombinant VWF-eGFP (rVWF-eGFP) and VWF labeled with an FITC-conjugated polyclonal antibody are employed. Anti-P-Selectin FITC-conjugated antibodies and the calcium-sensitive probe Indo-1 are used to detect activated platelets. A positive correlation between the mean number of platelets detected per image and the percentage of activated platelets determined through flow cytometry is obtained, validating the technique. An increase in the number of rVWF-eGFP signals upon exposure to shear stress demonstrates the technique’s ability to detect breakup of self-aggregates. VWF globular and unfolded conformations and self-aggregation are also observed. The ability to track the size and shape of VWF-platelet strands in space and time provides means to detect pro- and antithrombotic processes.

Background. The breech extraction of the fetus through the vagina has a greater risk of hip fracture compared with the extraction by abdominal route. Case. A 2390 g female infant was delivered at 39 weeks by elective cesarean section for breech presentation. The newborn sustained a fracture of the right femur. A simple immobilization of the limb in extension led to a complete healing of the fracture without sequelae. Conclusion. Caesarean delivery reduces the risk of causing a traumatic injury of the newborn compared to vaginal delivery, especially with breech presentation but does not eliminate this possible accidental complication.

Background: Deficits in synaptic function and neurite connectivity are early correlates of tauopathies. Altered tau processing and mis‐localization coincide with reductions in synapse density and synaptic function, suggesting a causal role for tau in disease pathogenesis. In parallel, altered activity of hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, involved in synaptic integration, is implicated in disease progression in animal models of tauopathy. However, the mechanisms underlying these pathological events are not fully understood. Methods: We performed histological and biochemical analyses of hippocampal tissues from Alzheimer's disease (AD), age‐matched controls and Tau35 mice, in which a human tauopathy‐associated tau fragment is minimally expressed. Image analysis and quantification were performed on antibody‐labelled human and mouse hippocampal sections (Visiopharm). Brain tissue from Tau35 and wild‐type (WT) mice was also examined on western blots, by Golgi‐Cox staining and transmission electron microscopy. Primary hippocampal neurons from Tau35 and WT mice were transfected with a plasmid expressing enhanced green fluorescent protein (eGFP) and imaged up to 14 days in vitro. Three‐dimensional digital reconstruction of dendrites and spines enabled morphological analysis of eGFP‐expressing neurons. In parallel, patch‐clamp recordings were performed to assess functional changes and HCN channel activity in Tau35 neurons. Results: Here we show that HCN channels are functionally linked to tau abnormalities. Alterations in HCN channel expression are detected in both Tau35 mouse and human post‐mortem AD brain. Tau35 neurons exhibit altered synaptic cytoarchitecture, including progressive reductions in dendritic branching, pre‐synaptic vesicles, spine density and synaptic markers, along with the development of tau pathology. These changes are accompanied by functional abnormalities in network activity, including increased HCN‐dependent sag voltage, reduced frequency and slower kinetics of spontaneous excitatory postsynaptic currents. Conclusions: Our findings are consistent with the hypothesis that disease‐associated tau species impact on HCN channels to drive network‐wide structural and functional synaptic deficits, with significant therapeutic relevance for tauopathies. [ABSTRACT FROM AUTHOR]