Unlocking liver physiology: comprehensive pathway maps for mechanistic understanding.

Aims: methods provide a resourceful toolbox for new approach methodologies (NAMs). They can revolutionize chemical safety assessment by offering more efficient and human-relevant alternatives to traditional animal testing. In this study, we introduce two Liver Physiological Maps (PMs); comprehensive and machine-readable graphical representations of the intricate mechanisms governing two major liver functions.

A single-cell atlas of the murine limb skeleton integrating the developmental and adult stages.

The recent growth of single-cell transcriptomics has made single-cell RNA sequencing (scRNA-seq) into a near-routine technique. Breakthroughs in scalability have led to the creation of organism-wide transcriptomic datasets, aiming to comprehensively profile the cell types and states within an organism throughout its lifecycle. However, the skeleton remains an underrepresented organ system in organism-wide atlases.

From cellular perturbation to probabilistic risk assessments.

Chemical risk assessment is evolving from traditional deterministic approaches to embrace proba­bilistic methodologies, where risk of hazard manifestation is understood as a more or less probable event depending on exposure, individual factors, and stochastic processes. This is driven by advancements in human stem cells, complex tissue engineering, high-performance computing, and cheminformatics, and is more recently facilitated by large-scale artificial intelligence models. These innovations enable a more nuanced understanding of chemical hazards, capturing the complexity of biological responses and variability within populations.

TNF induces catabolism in human cartilaginous endplate cells in 3D agarose culture under dynamic compression.

Intervertebral disc (IVD) degeneration is the leading cause of low back pain in young adults, and the cartilaginous endplate (CEP) is likely to play a key role in early IVD degeneration. To elucidate the effects of pro-inflammatory cytokines on the mechanobiology of the CEP, human CEP cells were seeded into 2% agarose, dynamically compressed up to 7%, and stimulated with tumor necrosis factor (TNF). It was hypothesized that dynamic compression would be sufficient to induce anabolism, while stimulation with TNF would induce catabolism.

In Silico Scenario of Bare Metal Stent and Drug-Eluting Stent Performance modeling in Patient-Specific Arteries: A Comparative Analysis.

Atherosclerosis, a chronic inflammatory disease linked to heart attacks and strokes, stimulates the formation of atherosclerotic plaques within arterial vessels, leading to reduced blood flow to the heart. Drug-Eluting Stents (DES) aim to expand the arterial stenosis and restore the blood flow while mitigating neo-intimal thickening through controlled drug release. In silico modeling has been widely used as a reliable means to predict and evaluate stent performance accurately.

In silico drug delivery modeling of a novel Everolimus Coated Balloon.

This study examines the drug elution process of a novel Everolimus Coated Balloon (ECB) that features a novel polymer mixture consisting of cellulose derivatives and accelerators, and Everolimus as the pharmaceutical component, based on commercially available PTCA balloon-catheter system. In this analysis, we utilized in silico postdeployment results comprising three distinct datasets of healthy porcine arteries undergoing PTCA with (a) Sirolimus, (b) Low-dose Everolimus, and (c) High-dose Everolimus. We developed a computational model that consists of the drug release from the balloon surface and the drug transport through the porous arterial wall given advection and diffusion properties.

Targeting uPARAP Modifies Lymphatic Vessel Architecture and Attenuates Lymphedema.

Background: Lymphedema is an incurable disease associated with lymphatic dysfunction that causes tissue swelling and fibrosis. We investigated whether lymphedema could be attenuated by interfering with uPARAP (urokinase plasminogen activator receptor-associated protein; gene), an endocytic receptor involved in fibrosis and lymphangiogenesis.

Methods: We generated mice with lymphatic endothelial cell (LEC)-specific deficiency and compared them with constitutive knockout mice by applying a preclinical model of secondary lymphedema (SL).

Mapping physiology: A systems biology approach for the development of alternative methods in toxicology.

Chemical safety assessment still heavily relies on animal testing, which is associated with ethical dilemmas and has limited human predictive value. New approach methodologies (NAMs), including in vitro and in silico techniques, offer alternative solutions. In silico toxicology has made progress in predicting chemical effects but frequently lacks biological mechanistic founda­tions.

A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification.

Low-grade inflammation and pathological endochondral ossification are key processes underlying the progression of osteoarthritis, the most prevalent joint disease worldwide. In this study, we employed a multi-faceted approach, integrating publicly available datasets, analyses, experiments and models to identify new therapeutic candidates targeting these processes. Data mining of transcriptomic datasets identified EPHA2, a receptor tyrosine kinase associated with cancer, as being linked to both inflammation and endochondral ossification in osteoarthritis.

Immune digital twins for complex human pathologies: applications, limitations, and challenges.

Digital twins represent a key technology for precision health. Medical digital twins consist of computational models that represent the health state of individual patients over time, enabling optimal therapeutics and forecasting patient prognosis. Many health conditions involve the immune system, so it is crucial to include its key features when designing medical digital twins.

Advancing in Silico Clinical Trials for Regulatory Adoption and Innovation.

The evolution of information and communication technologies has affected all fields of science, including health sciences. However, the rate of technological innovation adoption by the healthcare sector has been historically slow, compared to other industrial sectors. Innovation in computer modeling and simulation approaches has changed the landscape in biomedical applications and biomedicine, paving the way for their potential contribution in reducing, refining, and partially replacing animal and human clinical trials.

Reversing the relative time courses of the peptide bond reaction with oligopeptides of different lengths and charged amino acid distributions in the ribosome exit tunnel.

The kinetics of the protein elongation cycle by the ribosome depends on intertwined factors. One of these factors is the electrostatic interaction of the nascent protein with the ribosome exit tunnel. In this computational biology theoretical study, we focus on the rate of the peptide bond formation and its dependence on the ribosome exit tunnel electrostatic potential profile.

Influence of physicochemical characteristics of calcium phosphate-based biomaterials in cranio-maxillofacial bone regeneration. A systematic literature review and meta-analysis of preclinical models.

Objectives: Calcium phosphate-based biomaterials (CaP) are the most widely used biomaterials to enhance bone regeneration in the treatment of alveolar bone deficiencies, cranio-maxillofacial and periodontal infrabony defects, with positive preclinical and clinical results reported. This systematic review aimed to assess the influence of the physicochemical properties of CaP biomaterials on the performance of bone regeneration in preclinical animal models.

Methods: The PubMed, EMBASE and Web of Science databases were searched to retrieve the preclinical studies investigating physicochemical characteristics of CaP biomaterials.

The coming decade of digital brain research: A vision for neuroscience at the intersection of technology and computing.

In recent years, brain research has indisputably entered a new epoch, driven by substantial methodological advances and digitally enabled data integration and modelling at multiple scales-from molecules to the whole brain. Major advances are emerging at the intersection of neuroscience with technology and computing. This new science of the brain combines high-quality research, data integration across multiple scales, a new culture of multidisciplinary large-scale collaboration, and translation into applications.

Development of 3D Printed pNIPAM-Chitosan Scaffolds for Dentoalveolar Tissue Engineering.

While available treatments have addressed a variety of complications in the dentoalveolar region, associated challenges have resulted in exploration of tissue engineering techniques. Often, scaffold biomaterials with specific properties are required for such strategies to be successful, development of which is an active area of research. This study focuses on the development of a copolymer of poly (N-isopropylacrylamide) (pNIPAM) and chitosan, used for 3D printing of scaffolds for dentoalveolar regeneration.

Robotics-Driven Manufacturing of Cartilaginous Microtissues for Skeletal Tissue Engineering Applications.

Automated technologies are attractive for enhancing the robust manufacturing of tissue-engineered products for clinical translation. In this work, we present an automation strategy using a robotics platform for media changes, and imaging of cartilaginous microtissues cultured in static microwell platforms. We use an automated image analysis pipeline to extract microtissue displacements and morphological features as noninvasive quality attributes.

Cartilaginous endplates: A comprehensive review on a neglected structure in intervertebral disc research.

The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain.

Model-Based Design to Enhance Neotissue Formation in Additively Manufactured Calcium-Phosphate-Based Scaffolds.

In biomaterial-based bone tissue engineering, optimizing scaffold structure and composition remains an active field of research. Additive manufacturing has enabled the production of custom designs in a variety of materials. This study aims to improve the design of calcium-phosphate-based additively manufactured scaffolds, the material of choice in oral bone regeneration, by using a combination of in silico and in vitro tools.

COMMBINI: an experimentally-informed COmputational Model of Macrophage dynamics in the Bone INjury Immunoresponse.

Bone fracture healing is a well-orchestrated but complex process that involves numerous regulations at different scales. This complexity becomes particularly evident during the inflammatory stage, as immune cells invade the healing region and trigger a cascade of signals to promote a favorable regenerative environment. Thus, the emergence of criticalities during this stage might hinder the rest of the process.

Position paper From the digital twins in healthcare to the Virtual Human Twin: a moon-shot project for digital health research.

The idea of a systematic digital representation of the entire known human pathophysiology, which we could call the Virtual Human Twin, has been around for decades. To date, most research groups focused instead on developing highly specialised, highly focused patient-specific models able to predict specific quantities of clinical relevance. While it has facilitated harvesting the low-hanging fruits, this narrow focus is, in the long run, leaving some significant challenges that slow the adoption of digital twins in healthcare.

Coupling biomechanical models of implants with biodegradation models: A case study for biodegradable mandibular bone fixation plates.

In fracture fixation, biodegradable implant materials are an interesting alternative to conventional non-biodegradable materials as the latter often require a second implant removal surgery to avoid long-term complications. In this study, we present an in silico strategy to design/study biodegradable metal implants focusing on mandibular fracture fixation plates of WE43 (Mg alloy). The in silico strategy is composed of an orchestrated interaction between three separate computational models.

A simple geometrical model of the electrostatic environment around the catalytic center of the ribosome and its significance for the elongation cycle kinetics.

The central function of the large subunit of the ribosome is to catalyze peptide bond formation. This biochemical reaction is conducted at the peptidyl transferase center (PTC). Experimental evidence shows that the catalytic activity is affected by the electrostatic environment around the peptidyl transferase center.

An Empirical Model Linking Physico-Chemical Biomaterial Characteristics to Intra-Oral Bone Formation.

Facial trauma, bone resection due to cancer, periodontal diseases, and bone atrophy following tooth extraction often leads to alveolar bone defects that require bone regeneration in order to restore dental function. Guided bone regeneration using synthetic biomaterials has been suggested as an alternative approach to autologous bone grafts. The efficiency of bone substitute materials seems to be influenced by their physico-chemical characteristics; however, the debate is still ongoing on what constitutes optimal biomaterial characteristics.

Stirred culture of cartilaginous microtissues promotes chondrogenic hypertrophy through exposure to intermittent shear stress.

Cartilage microtissues are promising tissue modules for bottom up biofabrication of implants leading to bone defect regeneration. Hitherto, most of the protocols for the development of these cartilaginous microtissues have been carried out in static setups, however, for achieving higher scales, dynamic process needs to be investigated. In the present study, we explored the impact of suspension culture on the cartilage microtissues in a novel stirred microbioreactor system.